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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"826",leadTitle:null,fullTitle:"Tumor Angiogenesis",title:"Tumor Angiogenesis",subtitle:null,reviewType:"peer-reviewed",abstract:"Tumor angiogenesis is the main process responsible for the formation of new blood vessels that promote tumor growth and metastasis. 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This book complies a series of reviews that cover a broad spectrum of current topics related to the pathology of tumor blood vessels including mechanisms inducing new vessels, identification of new targets for inhibition of tumor angiogenesis, and potential clinical use of known and novel anti-angiogenic therapies. 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A growing number of studies have explored the interaction between the nervous and immune systems during the development of neurological disorders. The central nervous system (CNS) is an environment considered “immunologically privileged,” as many antibodies and peripheral immune cells are blocked by the blood-brain barrier (BBB), a highly specialized brain endothelial structure composed of pericytes, astrocytes, and microglia, which does not allow the passage of peripheral immune cells and whose resident cells express little major histocompatibility complexes I and II (MHC-I and MHC-II) receptors, as well as low levels of pro-inflammatory cytokines. However, in damage situation, glial cells show increased expression of MHC, Toll-like receptors (TLRs), and proinflammatory cytokines (such as TNF-α, IFN-γ, IL-1β, and IL-6). Innate immune response mediated by glial cells seems to be crucial for the progression of many neurodegenerative diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), and Parkinson’s disease (PD). Thus, neuroimmunology emerged as an intersection between the nervous system disease mechanism and therapeutic targets.
The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling appears to play an essential role in inhibiting neuroinflammation and in preventing the activation of a proapoptotic pathway, thus promoting neural cell survival. Phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a potential therapeutic strategy to modulate neuroinflammation. Mechanistically, PDE5-Is exert anti-inflammatory and neuroprotection effects by inhibiting PDE5 with subsequent accumulation of cGMP and activation of protein kinase G (PKG). The objective of this chapter is to review present knowledge of the NO/cGMP signaling pathways on neuroinflammation and the potential therapeutic use of PDE5-Is on neurodiseases.
Cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) exert many physiological roles such as the regulation of ion channels, relaxation of smooth muscle, immunomodulation, inflammation, cell proliferation and apoptosis, insulin secretion and glycogen synthesis/glycogenolysis, lipogenesis and lipolysis steroidogenesis, phototransduction as well as neuronal survival, and consolidation of memory. Both cAMP and cGMP can alter cell function by activating or inactivating proteins by phosphorylation. The most important regulation of cyclic nucleotides is achieved in negative feedback by activating phosphodiesterases (PDEs), which hydrolyses the cAMP and cGMP in their inactive forms, 5ʹAMP and 5ʹGMP, respectively [1–3].
Synthesis of intracellular cAMP from adenosine 5ʹ-triphosphate (ATP) by membrane-bound adenylyl cyclase (AC) is mainly regulated by G proteins. The response to activation of G-protein-coupled receptors (GPCRs) transduces a variety of extracellular signals and then to intracellular signals, regulating cellular responses [4]. The key transducer of cAMP signals is the cAMP-dependent protein kinase A (PKA). Upon binding of cAMP to the regulatory PKA subunits, it dissociates into two free regulatory and two catalytic subunits. The liberated active catalytic PKA subunits can phosphorylate serine and threonine residues on substrate proteins, including the transcription factor cAMP-response element-binding protein (CREB). There are some alternative PKA-independent cAMP actions, such as the immunomodulatory effects in monocytes and macrophages of guanine exchange proteins directly activated by cAMP (EPAC-1 and EPAC-2) [5, 6].
Synthesis of cGMP is mediated by membrane-bound/particulate (pGC) and cytosolic/soluble (sGC) guanylate cyclases, which convert guanosine 5ʹ-triphosphate (GTP) into cGMP. sGC is activated by NO released by the endothelium and neurons, whereas pGCs (GC-A, GC-B, and GC-C) are activated by binding of specific peptides. GC-A present in the kidney is responsible for controlling natriuresis and blood pressure through stimulation by atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP), which are released from the heart. In the small intestine, GC-C stimulates secretion of fluids through activation by intestinal peptide, guanylin [7]. The physiological effects of cGMP activities are determined by three types of intracellular targets: cGMP-dependent kinases (PKG), cyclic nucleotide-gated channels, and cGMP-binding PDEs [8]. In some cell types, it modulates the concentration of cAMP by activating PDE2 or inhibiting PDE3 activity [9, 10].
cGMP plays an important role as a mediator of the action of NO. NO is highly reactive and unstable free radical, which regulates a variety of cellular functions by diffusion from its originating cell to surrounding cells [11]. The NO can be synthesized by three NO synthase (NOS) isoforms, namely, neuronal synthase (nNOS or NOS-I), inducible form (iNOS or NOS-II), and the endothelial form (eNOS or NOS-III). The constitutive isoforms, eNOS and nNOS, are anchored on the internal surface of the cell membranes, and their activities by the endothelial cells and neurons are responsible for maintenance of physiological homeostasis such as blood pressure and blood flow, platelet aggregation, leukocyte adhesion to the endothelium, and neuronal signaling. eNOS and nNOS produce NO under physiological conditions and are primarily regulated by intracellular Ca2+/calmodulin levels. The inducible isoform iNOS is Ca2+ independent and represents a newly synthesized enzyme, which is expressed in response to specific stimuli, such as endotoxin and cytokines. iNOS is present in macrophages, hepatocytes, smooth muscle, endothelium, and glial cells and produces NO after immunological stimulation [i.e., IFN-γ, TNF-α, lipopolysaccharide (LPS)]. Whereas eNOS and nNOS produce NO for a short period of time (seconds or minutes), iNOS produces NO for long period of time (hours to days) and typically synthesizes 100–1000 times more than constitutive NOS [12, 13]. At high levels, NO produced by iNOS exerts cytotoxic and pro-inflammatory effects; however, the low nanomolar concentrations of NO produced by the eNOS isoform exhibit anti-inflammatory effects via the cGMP signaling and perhaps other mechanisms [14, 15]. The NO pathway can inhibit vascular nuclear factor-kappaB (NF-κB), a key transcriptional mediator of inflammation, by increasing the expression of cytoplasmic and nuclear levels of its inhibitor, the IκB-α [16], or by directly inhibiting the NF-κB binding [17]. Moreover, eNOS regulates NF-κB expression in a negative feedback mechanism, limiting local inflammation [18].
Studies developed on knockout mice for NOS isoforms indicate that NO derived from eNOS and nNOS is critical in the regulation of leukocyte-endothelial cell interactions in postcapillary venules [19, 20]. NO produced by the vascular endothelium exerts a cytoprotective and antithrombotic role by preventing the activation and adherence of leukocytes and platelets. The anti-inflammatory effects of NO are mediated predominantly via the activation of sGC and subsequent formation of cGMP. The production of cGMP causes specific downregulation of the expression of P-selectin on endothelial cells and platelets to prevent leukocyte rolling, adhesion, and migration [21].
The NF-κB is the generic name of a family of transcription factors that functions as dimers and regulates gene expression of a plethora of inflammatory and immune mediators, including cyclooxygenase-2 (COX-2) and iNOS, both considered important mediators in the recruitment of inflammatory cells [22–24]. The NF-κB proteins are sequestered in the cytoplasm through physical interaction with IκB family proteins. Proinflammatory cytokines (IL-1, TNF-α), B- and T-cell activators, pathogen-associated molecular patterns (PAMPs), and oxidative stress activate IκB kinase (IKK), a cytoplasmic kinase complex, that phosphorylates the IκB molecules, leading to their subsequent degradation through the ubiquitin–proteasome pathway. NF-κB dimers then translocate to the nucleus where they can bind to κB consensus sequences and activates the transcription of various genes [4]
Cyclic AMP/PKA modulates the NF-κB function through several events; some of them include CREB-mediated transcription of the IκB gene, thus elevating the expression of resynthesized IκB, inhibiting IκB degradation via blocking of IKK activity, and enhancing IκB levels by interfering with Iκ ubiquitination and/or subsequent proteasomal degradation [25–28].
Intracellular levels of cGMP also exert a role in modulating inflammatory response. Initially, some studies demonstrated that inhibition of endogenous NO production markedly increased monocyte chemoattractant protein-1 (MCP-1) mRNA levels in endothelial cells, whereas exogenous addition of NO dose dependently decreased MCP-1 mRNA expression and secretion [29]. This NO modulating effect of MCP-1 expression occurs via suppression of NF-κB by reducing the degradation of IκB [30, 31]. In sequence, a detailed study described the NO/cGMP role in regulating the inflammatory response. According to Aiwaza and cols [9], NO and C-type natriuretic peptide (CNP) inhibit NF-κB activity via cGMP-dependent activation of PKA, but not of PKG. In summary, the cGMP elevated levels by NO donor or natriuretic peptide inhibited PDE3 activity, which lead to the increase of cAMP and activation of PKA. PKA inhibited NF-κB transcription activity and, subsequently, the downstream MCP-1 and vascular cell adhesion molecule-1 (VCAM-1) gene expressions.
Moreover, there are other mechanisms by which NO/cGMP regulates the NF-κB activation and MCP-1 expression, such as activation of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) and, ultimately, inhibition of p38 MAPK, suggesting a counter-regulatory action of p38 MAPK and NF-κB [32].
In addition to anti-inflammatory effects, NO can have both pro- and anti-tumorigenic activities depending on NOS uncoupling that can occur under some conditions, such as low [Arg] or elevated levels of endogenous NOS inhibitors. Uncoupled NOS produces oxidants like peroxynitrite and O2, which initiates different downstream signaling that for tumor cells are pro-proliferative and antiapoptotic, e.g., NF-κB. However, when the primary product of NOS is NO, downstream signaling is dominated by anti-tumorigenic NO-dependent pathways (sGC/cGMP/PKG) [33]. The NO/cGMP/PKG pathway appears to play an essential role in promoting apoptosis, thus inhibiting tumor growth. Activating cGMP/PKG pathway by PDE5 inhibitors selectively inhibits colon tumor growth, as well as the knockdown of PDE5 in colon cancer cell (HT-29) by siRNA efficiently promotes apoptosis and delayed proliferation [34, 35]. Recently, it was also demonstrated that increased intracellular levels of cGMP induced by the inhibition of PDE5 significantly inhibit colonic tumorigenesis dependent on inflammation [36].
However, NO/cGMP/PKG actions appear to be highly cell type and context dependent. In some neural cells, the NO/cGMP/PKG pathway has an essential role as an antiapoptotic/prosurvival factor [37]. This neuroprotective mechanism may be especially important during brain ischemia, inflammation, or trauma. In retinal neuroglial progenitor cells, NO/cGMP/PKG antiapoptotic cascade is activated through Akt-induced CREB1 activation [38, 39]. CREB is a transcription factor involved with neurotransmitters, growth factors, and other signaling molecules with essential functions for memory and neuronal survival [40, 41]. In cerebellar granule neurons, there is evidence that NO plays an active role in sustaining the neuronal survival through NO/cGMP/PKG [42].
cGMP/PKG1 is also considered as a key effector in cardioprotection induced by PDE5 inhibitors against ischemic injury in the infarcted heart and cardiomyocytes. The potential mechanisms include its antiapoptotic effect as is evident by increased phosphorylation of Akt (pAkt) and glycogen synthase kinase 3β (pGSK3β), Bcl-2 expression, and prevention of caspase-3/caspase-7 activation [43–45]. Other studies provided the evidence that PDE5 inhibition prolonged survival of transplanted of bone marrow-derived mesenchymal stem cells in ischemic heart via cGMP/PKG signaling, contributing to regeneration of the ischemic heart [46].
Several lines of evidence strongly suggest that neuroinflammation is a crucial process involved in the progression of neuronal degeneration, a common feature observed in several neurodegenerative disorders. Therefore, the involvement of the local innate immune response can be a very complex process, contributing to perpetuate the damage to the CNS [47].
In the inflammatory process, there is an increase in blood flow and vascular permeability, venular dilatation, and recruitment of cells to the inflammatory site. Reactive oxygen species (ROS) play an important role in the inflammatory process, including endothelial cell damage and increased microvascular permeability, chemotactic factor production, neutrophil recruitment, oxidation, and lipid peroxidation [48]. These inflammatory mediators play a regulatory role in the growth, differentiation, and activation of immune cells [49]. Glial cells (microglia, astrocytes, and oligodendrocytes) define brain homeostasis and are responsible for defense against neural tissue injury [50, 51].
Astrocytes constitute a very heterogeneous population of cells, which regulate pH, extracellular levels of ions, neurotransmitters, and energy metabolism. They are involved in the formation and functioning of BBB [52] and also actively participate in neurotransmission [53]. In situations of CNS damage, the typical response is some degree of reactive gliosis [54], an astrocytic response involving positive gene regulation of cytoskeletal proteins (e.g., glial fibrillary acid protein, GFAP), hypertrophy, hyperplasia, and rearrangement of astrocytes, which may form glial scars [50].
In addition, astrocytes play an important role in central immunity. The innate immune response is precisely adjusted by identifying the type of threat that is present. Molecular structures associated with the threat are recognized by pattern recognition receptors (PRRs). PRRs recognize PAMPs, expressed by bacteria, fungi, and viruses, or damage-associated molecular patterns (DAMPs), expressed by cells and tissues under stress or injury. One of the major classes of PRRs in mammals is TLRs. The response is rapid both to the presence of pathogens and to other types of damage to the tissue, activating the immune system, which releases cytokines and chemokines, and modulating the BBB [50].
Astrocytes express TLRs [55]. The brain and spinal cord of multiple sclerosis patients showed increased TLR3 and TLR4 in astrocytes in regions of inflammation [56]. Most TLRs, after detecting their respective ligands, initiate a signal that is mediated by the myeloid differentiation gene 88 (Myd88) and result in the activation of nuclear transcription factor NF-κB. Translocation of NF-κB to the nucleus culminates in the secretion of proinflammatory molecules (IL-1β, IL-6, TNF-α, and IL-12). Activated astrocytes may also produce chemokines that recruit microglial cells, lymphocytes, and dendritic cells to the site of injury [57].
In the astrocytic response, in addition to increased TLR4 levels, leading to the expression of a variety of chemokines and cytokines [55, 58], other important processes occur, such as alteration of intracellular calcium signaling. Under conditions that lead to neuroinflammation in the CNS, as in exposure to LPS, Ca2+ signaling in the astrocyte network is over activated, triggering astrocyte activation. The inhibition of the communicating junctions (gap junctions), with changes in intercellular Ca2+ waves and Na+/K+-ATPase activity, results in disorganization of the actin filaments (stress fibers) [58, 59], and these effects are hallmarks of astrocyte reaction on neuroinflammation.
Evidence indicates that the cGMP/PKG pathway is involved in the regulation of astrocytic activity [60]. The NO, through the cGMP/PKG, decreased intracellular Ca2+ in astrocytes, reducing intercellular Ca2+ waves [61]. In addition, cGMP inhibited IFN-γ-induced MHC-II expression, as well as the expression of LPS-induced matrix metalloproteinase-9 (MMP-9) and TNF-α in cultured astrocytes [13, 60, 62]. According to these studies, MMP-9 expression is dependent on extracellular signal-regulated kinase (ERK) activation via NF-κB. This data supports the hypothesis that the NO/cGMP/PKG pathway plays a role in astrocytic cells that contributes to the resolution of neuroinflammation.
Microglia constitute the cells that are part of the innate immune system and are therefore considered as the pathological sensors of the CNS damage. The phenotypic changes of the microglia after activation are functionally identical to those observed in macrophages [63, 64]. The physiological functions of microglia are important for the maintenance of homeostasis. In addition, they have been shown to be responsible for the secretion of neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF) [65] and for removing aggregates of proteins [66]. However, when exposed to infections, lesions, or dysfunction of the nervous system, microglial cells become activated. In the absence of pathology, the microglia “at rest” are small cells with long and thin processes (“branched phenotype”). When activated, the microglia loses the long extensions typical of the inactive microglia and exhibits ameboid extensions (“ameboid phenotype”) [67]. Protein Iba-1, expressed on the microglia surface, is used as a marker of its activated state [68]. This physiological transformation is associated with changes in the expression of surface receptors and the release of cytokines, which may contribute to the damage of synaptic plasticity and the neurodegenerative disease aggravation [69].
Activated microglial cells become a source of TNF-α, IL-1β, IL-1α, superoxide, NO, chemokines, and glutamate, which may promote neuronal death. TNF-α, secreted both by microglia and astrocytes, can directly promote neuronal death by binding to its corresponding receptors (TNFRs). Evidence indicates that TNF-α induces apoptosis of mature oligodendrocytes in inflammatory demyelinating diseases such as multiple sclerosis [61, 70] and plays a key role in neurodegeneration process observed in Parkinson’s and Alzheimer’s diseases [57].
An in vitro study using N9 microglial cells demonstrated that the treatment with the PDE5 inhibitor, sildenafil, suppressed NO, IL-1β, and TNF-α production induced by LPS, due to suppression of the MAPKs/NF-κB pathways through the inhibition of NADPH oxidase, mediated ROS generation [71]. These results indicate that cGMP accumulation as a result of PDE5 inhibition might participate in the inhibition of microglial activation.
Oligodendrocytes are myelinizing CNS cells that arise from oligodendrocyte progenitor cells (OPCs). OPCs differentiate in mature or myelinizing oligodendrocyte, fixing extensions in axons to generate the concentric membrane layers to produce myelin. The presence of oligodendrocytes is more common in the white matter of neuronal tissue, such as the corpus callosum and cerebellum, and less frequent in gray [72]. In both compartments, myelin is necessary for the saltatory conduction of action potentials along axons [73].
Oligodendrocyte dysfunction and myelin abnormalities are found in a wide variety of neurological diseases and may be involved in the pathophysiology of various diseases, including genetic leukodystrophies [74], schizophrenia and bipolar disorder [75, 76], brain injury [77], and endocrine and metabolic abnormalities [78, 79] and neurodegenerative conditions such as strokes [80, 81], Parkinson’s disease [82], Alzheimer’s disease [83–85], multiple sclerosis [86], and diabetic encephalopathy [87].
In an attempt to repair myelin damage, increased differentiation of OPCs into mature oligodendrocytes promotes remyelination [88]. In later stages of injury, however, OPCs also enter into apoptosis. Recent studies have shown that treatment with sildenafil increases the levels of the protein expressed by oligodendrocytes, myelin basic protein (MBP), and also restores myelin sheath morphology, indicating remyelination. In addition, sildenafil induces the differentiation of OPCs into mature oligodendrocytes, as demonstrated by the increase of glutathione S-transferase pi (GST-pi, a marker of mature oligodendrocytes), indicating that cGMP signaling can modulate OPC survival and myelin production [89].
Oligodendrocytes are not inert immune cells, but secrete a wide variety of inflammatory mediators, such as the proinflammatory cytokines IL-1-β and IL-6 and CCL-2 and IL-8 chemokines involved in the recruitment of immune cells during inflammation [90]. In experimental multiple sclerosis models, oligodendrocytes in apoptosis also express increased levels of COX-2 at the demyelination beginning, which seem to make these cells more susceptible to death by glutamate-mediated excitotoxicity [91].
Faced with rising costs for the development of new drugs, researchers are looking for ways to repurpose older ones. Taking medications that have been developed for one disorder—and even some that fail in initial trials—and “repositioning” them to tackle another are a growing strategy for researchers in industry and academia [92].
The administration of selective PDE5-Is increases the levels of cGMP [93, 94], with effects on multiple organs and systems. The PDE5-I, sildenafil, is a medication for angina pectoris developed in 1989 [92]. For many years, sildenafil (Viagra®, Pfizer) has been the most representative molecule of the class of drugs to treat erectile dysfunction (ED) [95]. Under the trade name Revatio® (Pfizer), it was also approved for pulmonary artery hypertension therapy in June 2005 [96] and, more recently, for the Raynaud’s phenomenon [97]. Therefore, sildenafil is a classic success story of repositioning.
PDE5 is present throughout the body and brain [95, 98] and has emerged as a potential therapeutic target for diseases related to neuroinflammatory and neurodegenerative processes because of its reported relation with them (for review, see [99]). To date, only four PDE5-Is have been approved by the US Food and Drug Administration (FDA) and by the European Medicines Agency: sildenafil, vardenafil, tadalafil, and avanafil. Sildenafil is reported to clearly cross the BBB [100], whereas evidence for vardenafil is indirect [101] and, while it was first considered that tadalafil does not cross it [102], later was demonstrated that this drug is able to cross the barrier [103]. Several studies indicate that sildenafil and other PDE5-Is may offer novel strategies for the treatment of neurological pathologies [12, 102, 104]. The beneficial effects of PDE5-Is were initially attributed to its mechanism in smooth muscle (regulating blood flow) and improving synaptic plasticity and neurogenesis. However, recent studies point to an important effect of these drugs on neuroinflammation, which may be, at least in part, responsible for their protective effects on central neurological diseases.
Thus, five major mechanisms of PDE5-Is have been described in neurological disease models: (1) by modulating the CREB pathway, inducing the formation of new synaptic connections and neurogenesis, improving cognition and memory; (2) through the modulation of Akt/GSK3β and calpain/p25/CDK5 pathways, decreasing aggregate formation of proteins; (3) through apoptosis inhibition; (4) by inducting angiogenesis and improving blood flow; and (5) through the modulation of neuroinflammation. Targeting multiple elements in the network underlying complex diseases, such as neurological diseases, may produce benefits beyond those of representative monotherapies [105, 106]. Repositioning PDE5-Is as therapeutic approaches that can be used in combination with other drugs can therefore be useful. This section aims to name and classify representative preclinical and clinical studies of PDE5-Is in central neurological diseases (Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, Huntington’s disease (HD), and stroke) and to describe the main known mechanisms, with emphasis on neuroinflammation (following a search of the Medline®/PubMed® database, during the period between 2000 and 2016).
Alzheimer’s disease (AD) has become the fourth leading lethal disease among the elderly after cancer, heart disease, and stroke. It is an age-related neurodegenerative disease characterized by the presence of senile plaques (consisting of β-amyloid filaments, Aβ), neurofibrillary tangles (composed of hyperphosphorylated tau deposits), and neuronal degeneration accompanied by significant loss of synapses [107, 108] (Figure 1A). While early studies focused on assessing the beneficial effects of PDE5-Is on AD through the formation of synapses, neurogenesis, and protein aggregation pathways, more recent studies have shown that the role of these drugs in neuroinflammation may be an important mechanism in AD.
Hallmark pathologies of (A) Alzheimer’s disease (AD), (B) multiple sclerosis (MS), (C) Parkinson’s disease (PD), and (D) Huntington’s disease (HD). (A) In AD, neurons contain intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein and extracellular plaques of amyloid β (Aβ). The inflammatory reaction, with activation of microglia and astrocytes and the subsequent release of inflammatory cytokines and reactive oxygen species (ROS), plays a significant role in the pathological processing of AD. (B) MS is a chronic autoimmune/inflammatory disorder characterized by demyelination of axons, with associated acute and chronic inflammatory events involving the recruitment/activation of microglia/macrophages, astrocytes and B and T cells and release of proinflammatory cytokines, ROS, and autoantibodies. (C) In PD, neurons contain α-synuclein aggregates, forming Lewy bodies. Neuronal loss leads to lower production of dopamine. There is a persistent inflammatory response, T-cell infiltration, and glial cell activation in patients with PD and animal models, which play a crucial role in the degeneration of dopaminergic neurons. (D) In HD, mutant huntingtin protein (mhtt) containing an extended polyglutamine repeat, caused by at least 36 CAG repeats in the huntingtin gene, leads to intraneuronal aggregates. In all four diseases, the pathological events ultimately result in neuronal death. Over time, this either causes or contributes to neuroinflammation.
cGMP/PKG pathway contributes to phosphorylation of the transcription factor CREB; Prickaerts et al. [109] suggested that the cGMP/PKG/CREB pathway induces the synthesis of proteins essential for memory consolidation, probably through the formation of new synaptic connections [110]. Therefore, the chronic administration of PDE5-Is may lead to gene transcription through CREB activation, by raising cGMP levels (Figure 2A).
PDE5-I mechanisms in the CREB pathway and protein aggregation. (A) The PDE5 inhibitors (PDE5-Is) modulate the CREB pathway, increasing the expression of CREB and the downstream targets, BDNF, and Arc. The result is the induction of new synaptic connections and neurogenesis, leading to the restoration of pathological cognitive signs of neurological diseases, such as Alzheimer’s disease and Huntington’s disease. (B) PDE5-Is also modulate pathways involved in the protein aggregation. Calpain is an enzyme that cleavage p35 in its more stable isoform, p25. The formation of the p25/CDK5 complex is associated with tau hyperphosphorylation. In addition, p25/CDK5, via the downstream target BACE1, also leads to cleavage of amyloid precursor protein (APP), contributing to the formation of Aβ plaques. PDE5-Is induce a decrease in the activity of calpain, p25, and CDK5, with consequent decrease in protein aggregation. GSK3β is a kinase involved in the hyperphosphorylation of Tau. In addition, through the downstream target, cathepsin B, GSK3β leads to the formation of Aβ plaques. pAkt is a GSK3β inhibitor, modulating the pathway. PDE-Is increase Akt phosphorylation and decrease GSK3β activity and cathepsin B expression, which can contribute to control the protein aggregation.
Puzzo et al., in 2009 [102], and Cuadrado-Tejedor et al., in 2011 [111], showed that sildenafil has beneficial effects on AD models, modulating the CREB pathway. Puzzo et al. [102] demonstrated that sildenafil (3 mg/kg, i.p., for 3 weeks) may be beneficial against cognitive loss in the APP/PS1 mouse model of amyloid deposition, producing an immediate and lasting improvement of synaptic function, CREB phosphorylation, and memory. This effect was associated with a reduction in Aβ levels. Cuadrado-Tejedor et al. [111] showed that sildenafil (15 mg/kg, i.p., for 5 days) restored cognitive deficits in aged rat model of AD (Tg2576-AD transgenic mice); however, whereas pCREB was not significantly induced in mice treated with sildenafil, the BDNF and Arc (CREB downstream target molecules) increased, confirming that the drug acts through this pathway (CREB/BDNF/Arc), inducing synaptic formation and improving memory.
Cuadrado-Tejedor and coworkers [111] showed, however, that sildenafil did not affect Aβ-burden while decreased tau phosphorylation. The formation and aggregation of Aβ and tau involve some pathways, which can be plausible therapeutic target for the treatment of AD. GSK3β, which is inhibited by Akt, and cyclin-dependent kinase 5 (CDK5), which is activated by p25, are the most relevant kinases involved in the pathogenic mechanisms of AD by phosphorylation at multiple sites of the microtubule-binding protein, tau [112, 113]. The activities of GSK3β and CDK5 were reduced by sildenafil, whereas the drug increased Akt and decreased p25. The decrease in kinase activity of GSK3β and CDK5 due to sildenafil may lead to a reduction in tau phosphorylation, possibly contributing to the reestablishment of cognitive function (Figure 2B). Then, according to Cuadrado-Tejedor et al. [111], sildenafil reversed the marked memory deficits of elderly Tg2576 animals by regulating the Akt/GSK3β/pTau and p25/CDK5/pTau pathways, not resulting from any decrease in the Aβ-load. However, the contrasts between Cuadrado-Tejedor et al. [111] and Puzzo et al. [102] may be due to differences between dose, duration of treatment, and animal models. In addition, both Akt/GSK3β and p25/CDK5 signaling are also involved in the regulation of Aβ [114], and it is possible that if the treatment was longer, this effect would be detected.
Following the same line of investigation, Orejana et al. [114] treated senescence-accelerated mouse-prone 8 (SAMP8, used as a model of aging, which displays many established pathological features of AD) with sildenafil (7.5 mg/kg, i.p., for 4 weeks) and showed that the mechanism of protection is through Aβ decrease, by pAkt/GSK3β /cathepsin B pathway and calpain/p25/CDK5/BACE1 pathway inhibition. pAkt inhibits GSK3β, which is an important activator of cathepsin B [115]. Calpain is an enzyme that cleavages p35 in p25, and p25/CDK5 regulates BACE1 (protein cleaving enzyme 1) expression levels. BACE1 and cathepsin B (both β-secretases) cleavage amyloid precursor protein (APP), contributing to the formation of Aβ. Sildenafil decreased the activity of calpain, p25, and CDK5 and markedly increased Akt phosphorylation and decreased GSK3β activity. Consequently, sildenafil decreased the expression of BACE1 and cathepsin B, leading to a reduction in APP and Aβ levels (Figure 2B). These findings demonstrate that sildenafil modulates calpain/p25/CDK5/BACE1 and pAkt/GSK3β/cathepsin B pathways, and these mechanisms are probably responsible for beneficial effects of this class of drugs in AD models.
Although the first PDE5-I studies in AD models have been focused on synapse formation, neurogenesis, and memory improvement, investigating primarily CREB, tau phosphorylation, and Aβ formation pathways, more recent studies also point to an important anti-inflammatory mechanism of this class of drugs in AD. The work by Orejana et al. [114] was perhaps one of the first studies to suggest and demonstrate that sildenafil modulates inflammatory cells in AD model. They showed that sildenafil decreased the GFAP, a marker of astrogliosis. However, Orejana et al. [114] could not differentiate whether the reduction in GFAP levels resulted from less accumulation of Aβ or if it was a direct modulation of inflammatory events by sildenafil. A recent study using sildenafil in cultured astrocytes confirmed that sildenafil has a direct mechanism on neuroinflammation [116].
Until 2013, it was unknown whether PDE5-Is reversed Aβ-induced neuroinflammation in APP/PS1 transgenic mice. Zhang et al. [117] showed that APP/PS1 mice presented impaired cognitive ability, neuroinflammatory response in the hippocampus, and downregulated cGMP; sildenafil reversed memory deficits and cGMP/PKG/pCREB signaling dysfunction and reduced Aβ levels in this model. In addition, sildenafil decreased the proinflammatory cytokines IL-1β, IL-6, and TNF-α. The inhibition of hippocampal PKG immediately prior to the injection of sildenafil significantly blocked these effects, further indicating the participation of PKG in the anti-inflammatory effects produced by sildenafil (Figure 3A, B).
PDE5 inhibitors modulate neuroinflammation. (A) AMPK exerts its anti-inflammatory activity through multiple signaling pathways. The phospho-AMPK (pAMPK) suppresses NF-κB, by increasing its inhibitory protein, IKβ-α. Consequently, the production of cytokines is decreased. In addition, AMPK phosphorylates and activates eNOS, inducing NO production; eNOS increases AMPK, in a positive feedback, and NO can act as an endogenous activator of AMPK, suggesting a reciprocal relationship between AMPK and eNOS. eNOS also inhibits NF-κB, decreasing the inflammatory response. PDE5-Is increase pAMPK and eNOS expression, increase IKβ-α, and decrease NF-κB. NO activates sGC, inducing cGMP production, which can amplify the effect of PDE5-Is. (B) Some possible mechanisms of PDE5-Is in the control of neuroinflammation have been demonstrated while not fully understood. PDE5-Is increase levels of the chemokine MCP-1 and its receptor, CCR-2, which are typically overregulated in multiple sclerosis models. It is possible that this effect is indirect, through NO, since this gas was shown to increase MCP-1/CCR-2, but it has not been confirmed so far. In addition, PDE5-Is were shown to increase the three isoforms of nitric oxide synthase (nNOS, iNOS, and eNOS), along with increased levels of NO. However, the mechanism of NOS participation on the effects of PDE5-Is is unclear. ICAM-1 and VCAM-1 were decreased by PDE5-Is, which may be important for the control of leukocyte infiltration. It is possible that complex cross signaling is occurring, but although it has been demonstrated in inflammatory models, it has not been confirmed in preclinical studies with PDE5-Is in neurological diseases. For example, elevated levels of cGMP by NO may inhibit PDE3 activity, which leads to increased cAMP levels and PKA activation. PKA inhibits NF-κB transcription activity and, subsequently, the expression of downstream MCP-1 and VCAM-1.
An ongoing neuroinflammatory process has been considered a marker of AD [117]. The deposition of Aβ peptides and the activation of glial cells surrounding senile plaques in brain areas involved in cognitive functions are assumed to participate in the onset of a pathological cascade resulting in synaptic dysfunction, synaptic loss, and neuronal death [118, 119]. The inflammatory reaction, with activation of microglia and astroglia, and the subsequent release of inflammatory cytokines (IL-1β, TNF-α, and COX-2 and so on) play a significant role in the pathological processing of AD [108] (Figure 1A). Proinflammatory cytokines, such as TNF-α and IL-1β, may contribute to brain dysfunction and neurodegeneration, impair synaptic plasticity, and induce memory impairment, while the anti-inflammatory cytokine IL-4 has the opposite effect [120, 121]. NF-κB is well known as a key regulator that induces the expression of many proinflammatory cytokines and inducible effector enzymes linked to the inflammatory process. The degradation of IκB-α (NF-κB inhibitory protein) and NF-κB phosphorylation were enhanced after the Aβ injection [108].
Additionally to classical PDE5-Is, other drugs have been demonstrated to act on AD by inhibiting PDE5 and modulating neuroinflammation. It has recently been showed by Li et al. [108] that sodium hydrosulfide (NaHS), a hydrogen sulfide donor, decreased PDE5 levels, attenuated neuronal death, and suppressed apoptosis by inhibiting the activation of pro-caspase-3 in the hippocampus of Sprague-Dawley rats (injected with aggregated Aβ25-35). NaHS upregulated the expression of peroxisome proliferator-activated receptors (PPAR-α and PPAR-γ), which antagonize the effects of NF-κB [122]. Moreover, the Aβ25-35-injected rats exhibited a decrease in IκB-α degradation and an increase in NF-κB p65 phosphorylation levels, whereas these effects were attenuated by NaHS. NaHS can therefore act as an anti-inflammatory mediator by inhibition of PDE5.
A novel PDE5 inhibitor, Yonkenafil (yonk) (2, 6, or 18 mg/kg i.p.), given daily for 3 months, has been shown to have beneficial effects in APP/PS1 mice through anti-inflammatory mechanisms. Yonk reduced the area of Aβ plaques, increased neurogenesis, and inhibited over-activation of microglia and astrocytes [119]. A recent study by Yin et al. [123] has shown that Icariside II (ICSII), another new PDE5 inhibitor, derived from the Chinese herb
It was demonstrated by Jin et al. [124] that Icariin (ICA), a flavonoid extracted from Chinese herb (
Despite the rich (though recent) literature on the effects of the PDE5 inhibitors on animal models of AD, clinical studies are lacking. However, PCR analysis of postmortem tissue of patients suffering from AD found a considerable increase in PDE5 expression in the temporal cortex of the brain compared to healthy controls of the same age [129]. Also, it was observed that lower levels of cGMP in the cerebrospinal fluid of patients with AD were associated with cognitive decline and amyloid pathology [129]. In addition, a clinical study demonstrated that chronic administration of udenafil (Zydena; available in Korea, Russia, and the Philippines) to 27 patients with ED (100 mg at 3-day intervals for 2 month) has shown to lead to an improvement in cognitive function [130]. This has lead to suggest that sildenafil could improve cognitive function in AD patients.
Thus, the efficacy and safety of treatment with repeated doses of PDE5-Is have been demonstrated in several animal models of AD. Since the side effects of PDE5-Is are widely known and do not preclude its administration to a senile population, and considering the lack of effective treatments for AD, PDE5-Is have been proposed as potential alternatives as cognitive enhancers [99, 131].
Multiple Sclerosis (MS), the most common neurological disorder in young adults in the Western world, is a chronic autoimmune/inflammatory disorder characterized by demyelination of the nerve cells, which leads to severe psychomotor impairment [132]. CNS demyelination is frequently associated with acute and chronic inflammatory events involving the recruitment-activation of microglia/macrophages, astrocytes, and leukocytes, with the release of pro-inflammatory cytokines, ROS, and NO (Figure 2B) [133, 134]. Neuroinflammatory responses appear to begin before any significant loss of neuronal populations in the progression of MS [135].
It has been demonstrated that NO/cGMP signaling is involved in the regulation of neuroinflammation and myelination [89]. The intracellular accumulation of cGMP in different models of inflammation reduces the production of proinflammatory cytokines and oxidative stress, modulating the inflammatory response [136]. In addition, inhibition of PDEs seems to block the inflammatory response of microglia, reducing myelin sheath changes [137, 138]. Therefore, neuroinflammation mediated by glial cells (astrocytes and microglia) appears to be an important phenomenon that perpetuates neural damage in MS, and since cGMP-mediated pathways regulate inflammatory responses in immune and CNS cells, PDE5-Is are potential tools for treating MS.
In fact, it has been reported that patients suffering from ED, and in parallel MS, showed an improvement in clinical status for both pathologies after treatment with sildenafil [139]. The effect of sildenafil on improving the clinical status of patients with MS was initially attributed to the induction of neurogenesis [140]. However, studies have shown that sildenafil is a modulator of inflammation in the central and peripheral nervous systems and protects the myelin sheath both in pathological and healthy conditions [89, 116, 127, 128, 140–144]. This anti-inflammatory mechanism should better explain the protective effect of PDE5-Is in MS, considering the nature of the disease.
In 2011, Pifarré et al. [142] showed that sildenafil (10 mg/kg, s.c., for 18 days) reduced the clinical signs of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, developed in female C57BL/6 mice. Sildenafil prevented axonal loss and promoted remyelination. Furthermore, sildenafil decreased CD3+ leukocyte infiltration and microglial/macrophage activation in the spinal cord, while increasing T regulatory cells expressing fork head box transcription factor 3 (Foxp3 Tregs) and decreasing ICAM-1 in the infiltrated cells of the spinal cord. Autoreactive T cells infiltrating the CNS are the initiator and early effector cells in EAE development, but infiltrated macrophages, dendritic cells, and resident microglia constitute the ultimate effector cells that amplify neuroinflammation and tissue injury. ICAM-1, a type-1 membrane-bound glycoprotein expressed in the majority of leukocyte subtypes, endothelial and CNS glial cells, is involved in leukocyte entry, lymphocyte activation, and other immune responses and plays a central role in the development of MS and EAE [145, 146]. The decrease of ICAM-1 induced by sildenafil was also reported by Rapôso et al. [89]. Pifarré et al. [142] also showed that the presence of astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil, suggesting a possible mechanism for the restriction of the leukocyte dissemination in healthy parenchyma. However, this result does not corroborate other studies showing that PDE5-Is decrease GFAP expression and astrocyte activation [89, 114, 127, 140].
Continuing the investigation, Pifarré et al. [143] demonstrated that sildenafil treatment (10 mg/kg, s.c., for 18 days) preserved axons and myelin and increased the number of remyelinating axons in the EAE model; also, sildenafil protected immature and mature myelinating oligodendrocytes. However, if the protective effect of sildenafil on myelin and axons is secondary to its effect, controlling inflammation remains unknown. In addition, sildenafil upregulated YM-1, a marker of the macrophage/microglial M2 phenotype that has neuroprotective and regenerative properties, while Iba-1, a classical macrophage/microglial activation marker, was downregulated. In vitro analyses of spleen cells from sildenafil-treated animals showed downregulation of Th1/Th2/Th17 responses, while Tregs were upregulated and prevented accumulation of MOG-specific IgG2b in serum. These results suggest that sildenafil has a protective role, modulating central resident and peripheral immune cells.
A sequence of studies has characterized the effects and mechanisms of sildenafil in a cuprizone-induced demyelination and neuroinflammation in rodents, which has been widely used as a model of MS. Nunes et al. [140] and Rapôso et al. [127] demonstrated that sildenafil (25 mg/Kg administrated in the drinking water for 4 weeks) ameliorates cuprizone-induced demyelination in C57BL/6 mice. Sildenafil modulated the neuroinflammatory response (mediated by glial cells), reducing GFAP and Iba-1, IFN-γ, TNF-α, IL-1β, IL-2, and COX-2 expressions. However, the anti-inflammatory effect of sildenafil was abolished in the cuprizone model induced in iNOS−/− mice [127], showing that iNOS plays an important role in the mechanism of PDE5-Is. Sildenafil preserved the myelin and axons’ ultrastructure and elevated GST-pi, indicating that sildenafil protects mature oligodendrocytes. However, it is not clear if sildenafil induces oligodendrogenesis or if it inhibits cell death/apoptosis or both. Myelin protection and oligodendrocyte proliferation have also been demonstrated in ischemic models [147, 148], and several studies showed that PDE5-Is inhibit apoptosis in central neurological disease models [122, 148, 149].
Contributing to the understanding of the mechanism by which sildenafil acts in the control of neuroinflammation in MS model, Nunes et al. [128] investigated the involvement of the AMPK/Iκβ-α/NF-κB signaling pathway and the eNOS. AMPK, the regulatory protein of the lipid and glucose metabolism, is upregulated in activated astrocytes during reactive gliosis [150], whereas AMPK activators downregulate inflammation in vitro and in vivo in various animal models [151–153], and the loss of AMPK exacerbates the effects of EAE model [154]. The anti-inflammatory activity of AMPK is exerted through multiple signaling pathways, including phosphorylation and activation of eNOS and production of NO. NO may act as an endogenous activator of AMPK, suggesting a reciprocal relationship between AMPK and eNOS [155]. In addition, recent evidence suggests that the activation of AMPK can suppress NF-κB, thus contributing to the regulation of inflammation [71] (Figure 3A). Nunes et al. [128] showed that sildenafil treatment (25 mg/Kg administrated in the drinking water for 4 weeks) improved the clinical status of the cuprizone-MS mice model. The treatment reduced unphosphorylated (inactive) AMPK and increased phospho-AMPK (pAMPK, active). Moreover, sildenafil decreased NF-κB p65 expression and increased its inhibitory protein, IKβ-α. However, if AMPK induces NF-κB inhibition and which downstream targets may be involved in this inhibition require further investigation. The same study showed that sildenafil reduced the expression of GFAP, IL-1β, and TNF-α and increased the expression of the anti-inflammatory cytokine IL-10. Besides, the level of eNOS was increased by sildenafil, suggesting reciprocity between AMPK and eNOS. This study then provides evidence that sildenafil has anti-inflammatory effects probably through modulation of AMPK/IKβ-α/NF-κB signaling (Figure 3A). However, the involvement of downstream proteins, such as AMPK-SIRT1-NF-κB, and other pathways, such as MAPK-NF-κB, should also be further investigated. In addition, Nunes et al. [128] showed that eNOS may play a role in the sildenafil mechanism. The possible role of NOS in the mechanism of sildenafil corroborates with other studies [89, 124, 127].
The ongoing investigation, in 2016, by Nunes et al. [141] demonstrated that sildenafil increased levels of the chemokine MCP-1 and its receptor, CCR-2, in the cuprizone-induced MS model. This may be part of the anti-inflammatory mechanism, since CCR-2 is a chemokine closely related to the pathology of MS and MS-animal models. In general, during the first weeks of cuprizone exposure, it undergoes a typical overregulation of the chemokine, and both microglia and astrocytes produce CCR-2 [156]. Also, an increase in CCR-2 may be associated with a reduction of macrophage infiltrates after stroke, showing the neuroprotective effects of this receptor [157]. Moreover, mediators in the microenvironment define at what time microglia/macrophages can assume an active and phagocytic phenotype [157]. The expression of MCP-1/CCR-2 by glial cells may promote this change in microglia phenotype in an attempt to repair the injured environment [158]. Sildenafil can, therefore, modulate inflammation by playing a role in the regulation of glial cell morphology and activation through MCP-1/CCR-2 signaling (Figure 3B).
Borán et al. [60] estimated that stimulation of cGMP/PKG pathway acts beneficially in microglia, inducing the phagocytic phenotype (M2) and decreasing expression of inflammatory genes, in detriment to the proinflammatory phenotype (M1). The cGMP/PKG pathway stimulated the regulation of microglial cell morphology, inducing a dramatic reorganization of the actin cytoskeleton compatible with a protective phenotype, which is more effective in the removal of dead cells. cGMP-mediated pathways have been implicated in the regulation of the actin cytoskeleton and cell morphology in different cell types, including macrophages and astrocytes [159, 160]. Borán and García [160] demonstrated that the stimulation of the PKG pathway by NO regulates cytoskeleton dynamics and motility in cultured rat astrocytes, and evidence indicates that cGMP is involved in the regulation of astrocyte cytoskeleton through Na+/K+-ATPase activity, IP3 receptor (IP3R), and ankyrin B. Ankyrin B, a protein associated with the cytoskeleton, interacts with Na+/K+-ATPase and IP3R, connecting the pump to the Ca2+ responses from internal cell stores and to the integrity of the cytoskeleton [160] (Figure 4A). This suggests that stress fibers and Ca2+ waves could be changed by sildenafil. The involvement of the cytoskeleton in the sildenafil mechanism has been demonstrated by Nunes et al. [116]. Sildenafil induced Ca2+ response and a more organized actin fiber pattern in cultured astrocytes, compared to LPS stimulated cells. It is possible that the mechanism behind sildenafil effects in the cytoskeleton involves Na+/K+-ATPase, IP3R, and ankyrin B (Figure 4A). In addition, this study showed for the first time that sildenafil has astrocytes as target cells [116], confirming that the control of inflammation is not an indirect effect, secondary to neurogenesis, myelin repair, or improvement of blood flow.
Mechanisms of PDE5-Is in the cytoskeleton and in the apoptosis pathways. (A) PDE5-Is induce Ca2+ response and the stabilization of F-actin in astrocytes; however, the mechanism behind this effect is not elucidated. Na+/K+-ATPase interacts with ankyrin B, a cytoskeleton-associated protein, and with the IP3 receptor (IP3R) [coupled to the endoplasmic reticulum (ER) membrane], connecting the pump to the Ca2+ responses from internal cell stores and to the integrity of the cytoskeleton. It is possible that this mechanism contributes to the dramatic reorganization of actin cytoskeleton observed in microglia, macrophages, and astrocytes after stimulation of the cGMP/PKG pathway, leading to a more protective phenotype of these inflammatory cells. (B) PDE5-Is have an antiapoptotic effect by enhancing the expression of the antiapoptotic Bcl-2 protein and reducing the proapoptotic BAX and caspase-3 proteins. Whether the PDE5-Is mechanism involves caspase-mediated apoptosis by extrinsic and/or canonical intrinsic pathway is unclear. In the extrinsic pathway, the death receptor-ligand binds to the associated protein with death domain (FADD), which activates the initiator pro-caspase-8. Caspase-8 activates caspase-3, inducing apoptosis. The intrinsic apoptotic pathway is characterized by mitochondrial changes in response to various stress signals, such as severe genetic damage, hypoxia, and oxidative stress, which activate the initiator pro-caspase-9. Proapoptotic mitochondrial proteins, BH3-only members, activate other proapoptotic proteins, such as BAX, and antagonize antiapoptotic proteins, such as Bcl-2. Subsequently, the mitochondrial outer membrane is disrupted, and its permeability increases, resulting in cytochrome-c (Cyt-c) leakage into the cytosol. Cyt-c in the cytosol forms a complex with Apaf-1, called the apoptosome, which assists in auto-activation of initiator pro-caspase-9. Caspase-9 activates caspase-3, leading to apoptosis.
Although there is no clinical report investigating the use of sildenafil chronically in patients with MS, one study has shown the potential of the drug to improve motor impairment. Cocchiarella [161] chronically administrated sildenafil (100 mg per day for 7 month) to a 42-year-old man, who developed a generalized motor deficit with spasticity that made him a quadriplegic (but grew normally, including normal intellectual development). The diagnosis was inconclusive. Physical therapy evaluation for muscle strength and manual measures (scale from 0, no muscle activity whatsoever, to 5, muscle activity with full range of motion and against maximal resistance) by a physical therapist indicated a positive change in muscle activity, following sildenafil administration. After stopping the treatment, the patient kept all gains. The patient experienced common drug-induced events associated with sildenafil treatment, such as erection, headache, and nausea. This study indicates that sildenafil has potential to improve other motor deficiencies, such as MS.
Despite the autoimmune/inflammatory nature of MS that has already been described, the control of the disease through the use of immunosuppressant and immunomodulators has proven to be unsatisfactory. PDE5-Is, being sildenafil the most representative, are widely used and well-tolerated drugs, which may be a useful therapeutic intervention to ameliorate the neuropathology of MS. Therefore, well-designed clinical trials may demonstrate that oral administration of PDE5-Is can be appropriate for individuals with MS and other neuroinflammatory/neurodegenerative diseases, providing additional benefits to current treatments.
Parkinson’s disease (PD) is a common, slow-progressing neurological disorder that leads to a constant loss of motor function. Its clinical features include resting tremor, slow movements (bradykinesia), rigidity, impaired balance, difficulty initiating movement (akinesia), and loss of postural reflexes [162]. PD is characterized by the death of dopaminergic neurons in the substantia nigra, which results in the absence of dopamine release in striatum and therefore in motor impairment. The remaining neurons contain intracellular inclusions (Lewy bodies), composed of α-synuclein [163] (Figure 1C).
Studies by Uthayathas et al. [164] and by Janis et al. [165] evaluated the use of sildenafil as a neuroprotective agent in the murine model of PD induced by chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The hypothesis was that the cGMP accumulation would attenuate the loss of nigrostriatal dopamine neurons induced by the model. The analysis revealed that sildenafil did not prevent neurotoxicity and did not protect against dopamine depletion induced by chronic exposure to MPTP. Also, Uthayathas et al. [164] showed that a single dose of sildenafil (10 mg/kg i.p.) had no effect on fatigue as seen by swimming time. On the other hand, sildenafil did not produce any deleterious effects on nigrostriatal dopamine neuron function, nor did it potentiate the neurotoxic effects of MPTP, suggesting that sildenafil would not accelerate cell loss when used as a treatment of ED in men diagnosed with PD as this drug is used therapeutically to treat sexual dysfunction in PD patients. However, contradictorily, in 2010, a case report by Perkovic et al. [166] described choreoathetotic movements that were most likely induced by sildenafil in a 56-year-old patient with PD. The man presented strange, involuntary movements and anxiety after taking sildenafil 100 mg, 50 min after the last daily dose of levedopa/carbidopa. These adverse effects were considered to be elicited by the administration of sildenafil (drug abuse) in a previously stabilized responder to levedopa therapy. This effect may be a predisposition for pharmacokinetic interaction in short-time interval between levedopa and sildenafil applied in high dosage.
Despite these negative results using a single dose of sildenafil, therapy with the aim of modulating the immune response and neuroinflammation in PD, targeting microglia, astrocytes, and T cells, has recently been proposed [167]. Considerable evidence shows that persistent inflammatory response, T-cell infiltration, and glial cell activation [168, 169] are common features of human patients and animal models of PD and play a crucial role in the degeneration of dopaminergic neurons [170, 171] (Figure 1C). As a result, appropriate treatment appears to involve the ability to modulate peripheral and resident immune cells for the purpose of modifying inflammatory response. It is possible that the chronic modulation of neuroinflammation by PDE5-Is may be beneficial for PD. Clinical studies demonstrated that while a single dose of sildenafil does not cause a clear improvement in cognition in healthy adults [172], chronic administration of udenafil has shown to lead to an improvement in cognitive function [130]. This has led some to suggest that the therapeutic benefits of PDE5-Is may be better observed after chronic inhibition rather than after a single dose [173]. However, studies evaluating the anti-inflammatory effects of chronic PDE5-Is in PD models are lacking.
Investigation of the role of cGMP and PDE-Is in Huntington’s disease (HD) is also in the beginning. HD is a dominant hereditary neurodegenerative disorder, characterized by progressive impairment of cognitive and motor functions. This disorder is caused by a mutation that encodes an abnormal expansion of CAG-encoded polyglutamine repeats in a protein called huntingtin (htt) [174]. While healthy individuals contain 16–20 repeats, more than 36 are present within the htt gene in HD patients [175]. Toxic protein aggregates are also seen in HD patients, whose brains contain accumulations of mutated HTT protein (Figure 1D) [176]. The pathological hallmark of HD involves the loss of neurons in the cortex and striatum that lead to clinical manifestations including involuntary movements known as chorea, behavioral and psychiatric characteristics, and cognitive dysfunction. Mutant huntingtin (mhtt) has been reported to impair cAMP and cGMP/CREB signaling, a transcriptional pathway that has been hypothesized to play a critical role in HD pathology [177, 178].
It was demonstrated by Saavedra et al. [179] that hippocampal cGMP levels were threefold lower in R6/1mice (heterozygous transgenic mice in B6CBA background, expressing exon-1 of mhtt with 145 repeats), when they present deficits in object recognition memory and in passive avoidance learning. nNOS levels were also downregulated, while there were no changes in the levels of PDE5 and PDE9. A single i.p. injection of sildenafil (3 mg/kg), immediately after training, increased cGMP levels and improved memory in R6/1 mice. The same study demonstrated that cGMP levels were also reduced in the human HD hippocampus (six HD patients and five control cases). These results showed that the regulation of hippocampal cGMP levels may be a suitable treatment for cognitive impairment in HD [179]. Other studies have reported decreased levels of nNOS in the caudate of HD patients [180] and in the striatum and cortex of HD mouse models [181, 182]. It has to be investigated whether the mechanism of sildenafil protection in HD neural tissue is via NOS, as demonstrated in other neurological disease models [89, 124, 127, 128].
Puerta et al. [183] demonstrated that the PDE5-Is, sildenafil, and vardenafil (both 1.5 mg/kg p.o., given twice a day for 5 days) protected against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of HD (model induced in male Lewis rats). Rats treated with both sildenafil and vardenafil showed improved neurologic scores and reduced lesion volume. In addition, striatal pCREB levels along with the expression of the downstream target, BDNF, were significantly increased in sildenafil-treated rats, and sildenafil reduced death of GABAergic neurons in the brain tissue. In addition, the activation of calpain (involved in aggregates formation through calpain/p25/CDK5 pathway) was reduced, showing that this drug also can avoid huntingtin N-terminal fragment aggregates. The mechanism demonstrated by Puerta et al. [183] in the HD model is similar to that observed in several studies with AD models.
Also in 2013, Thakur et al. [184] showed that sildenafil was beneficial in the 3NP-HD model induced in Wistar rats, improving cognitive and motor functions. Sildenafil (2 and 4 mg/kg i.p., for 14 days) dose dependently restored body weight and improved memory performance and locomotor activity. The PDE5-I attenuated succinate dehydrogenase activity, balancing the cellular energy deficits induced by 3NP. In addition, as far as we know, this study showed for the first time (and was the only one to show) that sildenafil improves oxidative and nitrosative stress in HD model, indicating that inflammatory parameters may also be the target of this drug in HD.
Despite the lack of studies showing the role of PDE-Is in HD neuroinflammation, several studies carried out on postmortem HD brain tissue and mouse models of HD have found altered expression of immunologically active molecules in the CNS [185–187], and imaging studies indicated increased microglial activity in manifest and premanifest HD gene-expansion carriers [188, 189]. The mhtt leads to activation of microglia and complement, resulting in subsequent production and release of ROS, NO, and cytokines [190]. A study of 20 HD patients, of whom 5 were presymptomatic and 15 were symptomatic, as well as 16 age-matched healthy controls, showed that there were increased levels of IL-6, MMP-9, vascular endothelial growth factor (VEGF), and TGF-β1 in HD patients. These trends were further observed in a murine HD model [191]. Politis and coworkers [192] found an increase in the peripheral plasma levels of the pro-inflammatory cytokine IL-1β in HD gene carriers compared to normal controls; and increased microglial activation in the somatosensory cortex was associated with augmented plasma levels of IL-1β, IL-6, IL8, and TNF-α [193]. In addition, the biomarkers of inflammation were shown to be increased in the plasma of HD gene-expansion carriers, and upregulation was observed up to 16 years prior to expected onset [186, 187, 194], although, in a recent study, these findings were not confirmed [195]. On the other hand, Vinther-Jensen et al. [196] showed that biomarkers of neurodegeneration increased in manifest HD disease, but did not provide evidence of neuroinflammation in early pathogenesis of HD. Therefore, the involvement of neuroinflammation in the HD pathology is not confirmed. However, it is possible that inflammatory events begin years before the onset of the illness. This makes PDE5-Is potential tools to prevent HD development through modulating neuroinflammation, while it is only a speculation and studies need to be developed.
Therefore, despite the important role of neuroinflammation in PD and HD, there is a lack of studies using PDE5-Is to evaluate inflammatory parameters, making this an interesting field for exploration.
Although stroke is the third most common cause of death [197] and the leading cause of permanent disability in adults worldwide [198], the available therapeutic options remain very limited. As vasodilators with good hemodynamic effects, PDE5-Is have been considered potential tools to treat hypoxia and stroke. Due to this obvious effect, these drugs were initially investigated in stroke models considering their mechanisms in cerebral neovascularization and blood flow.
Several studies have shown that administration of sildenafil to animal models of stroke has beneficial effects [147, 199–201]. It was demonstrated that chronic sildenafil elevated cGMP levels in the brain [147], increased angiogenesis in the ischemic border regions, induced capillary-like tube formation, and increased VEGF [199]. Correspondingly, the relative cerebral blood flow in the lesion boundary area has also been improved [147, 200]. Sildenafil also evoked neurogenesis, increased neuronal and oligodendrocyte progenity, and reduced neurological deficits [147, 201]. However, the drug did not alter the size of the lesion [200, 201]. In contrast to these early works, Novitzky et al. [202] reported that sildenafil did not improve the conditions of C57BL/6 mice induced model of occlusion of the middle cerebral artery. However, in this study, sildenafil was given in a single peritoneal dose (Revatio®, Pfizer; 0.8 mg/ml), while in other ones, the drug was administered chronically.
To clarify the mechanism of PDE5-I protection in stroke model, a work by Barros-Miñones et al. [203] showed that sildenafil reduced the activation of calpain and CDK5 and increased the p25/p35 ratio, showing that the protective effects of sildenafil in the ischemia model are, at least in part, by similar mechanism observed in other neurological diseases. As described above, calpain cleaves p35 in its more stable isoform, p25. Cleavage of p35 to p25 and formation of the p25/CDK5 complexes are associated with aggregate formation (Figure 2B). As expected, sildenafil prevented tau hyperphosphorylation. This study also showed that sildenafil increased the expression of the antiapoptotic proteins Bcl-2 and Bcl-xL and reduced cell death. The effect of sildenafil on the decrease of apoptosis (through reduction of proapoptotic proteins Bax and caspase-3 expression and increasing the antiapoptotic protein Bcl-2) has also been demonstrated in physiological aging mouse model [149] (Figure 4B).
Following the same sequence of investigation of other neurological conditions, more recent studies have shown that the role of sildenafil in promoting stroke recovery is, at least in part, related to the anti-inflammatory mechanism. In 2014, Charriaut-Marlang et al. [148] surgically induced ischemia model in P7 Sprague-Dawley rat pups by occlusion in the right common carotid artery and tested sildenafil. The animals were treated with a single dose of Viagra®(Pfizer, 10 or 5 mg/kg i.p.). They found that sildenafil increased mean blood flow, reduced brain tissue loss, and decreased apoptosis (demonstrated by TUNEL). In addition, sildenafil increased the index of myelinated fiber density and improved motor capacity. Associated with these beneficial effects, sildenafil had anti-inflammatory effects, reducing astrogliosis and GFAP-positive cell density and decreasing microglial density. A very recent study by Moretti et al. [204] also demonstrated that sildenafil modulates neuroinflammation in the ischemia model induced in C57BL/6 mice P9 pups by permanent middle cerebral artery occlusion. Animals were treated with a single dose of sildenafil (Viagra®, Pfizer, 10 mg/kg i.p., given 5 min after artery occlusion), which provided a reduction of the mean lesion 8 days after ischemia; also, it reduced the number of GFAP-positive cells, decreased microglial density, and modulated the M1 and M2 profiles of microglia/macrophages in the late phase after ischemia. The number of activated microglia/macrophages (M2) increased 72 h after artery occlusion, while it decreased 8 days after ischemia in sildenafil-treated animals. However, despite the clear anti-inflammatory action of sildenafil in ischemic model, the mechanism behind this effect is still unexplained.
A reported clinical study by Silver and coworkers [205] tested the chronic administration of sildenafil (25 mg per day, for 90 days) in ten ischemic stroke patients aged 18 to 80 years, with a score of 2 to 21 (mild to moderately severe stroke; National Institutes of Health Stroke Scale, NIHSS). Sildenafil appeared to be safe in this group of patients, and all of them presented an improvement from baseline NIHSS score. However, despite the success in preclinical and some clinical studies, PDE5-Is have not been more fully investigated in studies with humans and have not moved into clinical practice until now.
In conclusion, the relevant role of NO/cGMP signaling in the control of neuroinflammation and in the modulation of glial cell activity has lead researchers to investigate the effects of PDE5 inhibitors on central neurological diseases. These drugs (sildenafil being the most representative and studied among them) have been shown to be safe and effective in the treatment of central neurological disorders, and its mechanisms have been clarified. Modulation of neuroinflammation appears to be a relevant mechanism of PDE-Is, mainly in chronic treatments, whereas it has to be more fully investigated. Despite the safety and benefits of this class of drugs administrated chronically to patients and the success in preclinical studies, there are no Phase I and Phase II clinical trials, which need to be developed to move forward the repositioning of PDE5-Is as therapy to treat neurological diseases.
Authors would like to thank the following Brazilian foundations for financial support: Oswaldo Cruz Foundation (FIOCRUZ/PROEP; #1572.2.10/15), Fundação de Amparo à Pesquisa do Estado de São Paulo (the São Paulo Research Foundation) (FAPESP; #2015/04194-0, #2016/15827-6), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (the Brazilian National Council for Scientific and Technological Development) (CNPq; #431465/2016-9, #303514/2015-9), and the Instituto Nacional de Ciência e Tecnologia de Neuroimunomodulação (INCT-NIM; #465489/2014-1).
Alzheimer’s disease (AD) is a complex neurological disease, which already in its earliest clinical phase is characterized by remarkable memory impairment. Multiple pieces of evidence suggest that in AD, memory impairment begins with dysfunction of synapses, a unique characteristic of nerve cells. Early neurochemical analyses of AD brain tissue revealed that the deficits in numerous neurotransmitters (including corticotropin-releasing factor, somatostatin, GABA, and serotonin) and the early symptoms correlate with dysfunction of cholinergic and glutamatergic synapses [1]. In addition to the deficits of the transmitters, many other biochemical and morphological indicators suggest that in early AD, synapses are under attack as reviewed in [2]. It has been shown that in biopsied AD cortex, there is a significant decrease in the numerical density of synapses in the brain and the number of synapses per cortical neuron [3]. The amyloid cascade hypothesis, one of the widely accepted theories, suggests that progressive accumulation and aggregation of amyloid-β proteins (Aβ) could be the main cause of AD, which triggers AD neuropathology. Aβ proteins are the proteolytic products of amyloid precursor protein (APP), a type-I transmembrane protein which is highly expressed in neurons, known to regulate synaptic function and neurite outgrowth [4]. There are two main alternative enzymatic pathways to process APP [5]:
Non-amyloidogenic pathway, where APP is subjected to consecutive cleavage by α-and γ-secretases that cut APP within the Aβ fragment
Amyloidogenic APP pathway, where APP is subjected to cleavage by β-and γ-secretases generating Aβ, a mix of short peptides ranging from 38 to 43 amino acids in length able to form polymorphous aggregates, so-called oligomers, and fibrils [6]
APP processing is regulated by neuronal activity, and neuronal activity may favor β-secretase-mediated amyloidogenic cleavage of APP during which Aβ proteins are generated [7]. It was accepted that after APP cleavage, Aβ peptides are first secreted, and then, extracellularly, soluble Aβ peptides aggregate into amyloid plaques. This extracellular Aβ, which is the main constituent of amyloid plaques, is thought to be toxic to the neurons. More recently, the intraneuronal Aβ has been demonstrated and reported to be involved in neuronal damage [8, 9]. It has been demonstrated that Aβ attacks synapses, small membranous protrusions that permit one neuron to pass a signal (electrical or chemical) to another neuron.
\nIt has been shown that synaptic activity may affect Aβ secretion [5], and it has been hypothesized that synaptic activity may stimulate the generation of Aβ although why this occurs and whether Aβ might have a normal function in neuronal synapse have not been understood well [10]. Strikingly, it has been shown that Aβ selectively binds to synapses when added to cultured neurons [11]. Further, the level of Aβ is shown to be increased in synaptosomes in early AD [12]. Immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive damage of neurites and synapses [13]. Thus, synapses could be sites of early accumulation of pathogenic Aβ. It is believed that soluble Aβ oligomers rather than monomeric or fibrillar Aβ are the main neurotoxic species. However, a structure of neurotoxic Aβ oligomers and the nature of their effects on synapses are not identified [14].
\nDespite advances, the efforts to target neurotoxic Aβ oligomers in the brain are confounded by high polymorphism of amyloid structures [15]. Oligomer specific antibodies may interact mainly with a specific type of Aβ conformers against which these antibodies were produced [16]. Therefore, to target polymorphic Aβ oligomers, a cocktail from several antibodies might be required. Another way to modulate Aβ aggregation could be via establishing H-bond interactions [17] to favor the formation of less toxic Aβ species [18].
\nTo fight a brain disease such as AD pathology, both synapse protection and anti-amyloid modulation would be desired properties of a possible therapeutic drug. However, to protect synapses and to modulate Aβ aggregation, amyloid aggregation modulator and neuroprotective therapeutics have to be delivered to the synapse. One way to deliver both therapeutic molecules is to use a compound which may carry both molecules simultaneously. Such multifunctional compound could be a dendrimer.
\nDendrimers are three-dimensionally branched, globular macromolecules built by a series of iterative steps from a small core molecule which defines the type of the dendrimer [19]. They were first synthesized and described in 1978 [20], and since then dendrimers are in focus, due to their outstanding complexation properties. The most important features of dendrimers are controlled molecular structure, nanoscopic size, and high tunable availability of multiple functional groups at the dendrimer surface. Dendrimers are composed of three elements: a core branched dendron and terminal groups which could be used for dendrimer functionalization. The number of surface functional groups of the dendrimer depends on the degree of dendrimer branching (Figure 1). For example, PPI or PAMAM dendrimers of the second generation have 16 functional groups on their surface, the third generation has 32, and the fourth dendrimer generation has 64 functional groups. Strikingly, the number of terminal groups increases exponentially, while the size increases linearly. The terminal groups on the dendrimer surface can be used for surface modification and dendrimer functionalization. Such modifications could change dendrimers’ surface charge and, for example, reduce toxicity associated with a cationic surface charge as reviewed by Appelhans et al. [23]. Dendrimers are most commonly synthesized using divergent or convergent different synthetic pathways [24]. Importantly, the high tunability of dendrimers’ surface allows endless possibilities for dendrimers’ biomedical applications, for example, for pharmaceutical applications, the terminal groups can be functionalized with different active conjugates such as specifically targeting antibodies, drugs, metal ions or imaging agents, and more [25]. Moreover, several research groups demonstrated that some types of dendrimers are able to cross the BBB [22, 26, 27, 28], showing their applicability for the research and possibly treatment of brain diseases.
\nStructure and chemical modification of dendrimers. (A) Molecular structure of poly(propylene imine) dendrimers of the fourth generation. Circle 1 shows the core; circle 2 indicates branching points of the dendrimers; circle 3 shows the terminal groups, R1 and R2. Fifth-generation PPI dendrimer (Eindhoven, the Netherlands) was renamed as fourth-generation (G4) PPI dendrimers following the uniform nomenclature [
In the present chapter, I summarize the experimental evidence showing that functionalized poly(propylene imine) dendrimers may provide multitargeting properties for dendrimers increasing their potential for the treatment of AD.
\nAccording to the amyloid cascade hypothesis, Aβ peptides are important players triggering the AD development. Multiple in vitro studies have demonstrated that the Aβ peptides can form fibrils and other aggregates called oligomers. The formation of insoluble Aβ fibril follows a nucleation-dependent polymerization mechanism (Figure 2) as described [29]. The formation of soluble Aβ oligomers in vivo is largely unknown; it is believed that soluble Aβ oligomers may precede fibril formation [30] and are more toxic than mature Aβ fibrils [31].
\nExample of amyloid fibrils and amyloid oligomers. (A) Electron micrographs of the Aβ(1–40) fibrils (B) Aβ(1–40) oligomers prepared as described [
In the search for drugs that would inhibit neuronal death in Alzheimer’s disease, one of the ways one can use is to find compounds that interfere with Aβ, cleaning the brain tissues from neurotoxic Aβ oligomers. It has been demonstrated that PPI dendrimers modified with maltose are capable of interfering with the amyloid formation in vitro [18, 28, 32, 33]
Characteristic aggregation curve for amyloid fibril formation. Sigmoid-shaped curve 5 μM recombinant Aβ(1–42) kinetics as detected by ThT fluorescence over time and displayed as % of total ThT binding. Area (A) corresponds to the lag phase (nucleation), area (B) corresponds to the growing phase, and area (C) corresponds to final ThT fluorescence plateau. Inset: molecular structure of ThT.
PPI dendrimers modified with maltose may, in the case of Aβ(1–40) or Aβ(1–42), interfere with amyloid fibril formation in a concentration-dependent manner, indicating that maltose PPI dendrimers bind amyloid proteins [18]. Figure 4 demonstrates the ThT fluorescent kinetics of Aβ(1–40) and Aβ(1–42) in the presence of maltose PPI dendrimers. As expected, Aβ alone forms the typical amyloid fibrils [30]. However, when the maltose PPI dendrimers are present, the morphology of amyloid fibrils is altered, demonstrating binding of the dendrimers to Aβ [18, 28, 35, 36]. The electron micrograph shows the morphology of amyloid fibril in the presence of maltose PPI dendrimers. Fibril clumps were generated by incubating maltose PPI dendrimers with Aβ(1–40). As it has been suggested that dendrimers interact with Aβ thus, fibrils seem to be varnished by maltose dendrimers and clumped together, and importantly, no Aβ oligomers were observed in the presence of maltose PPI dendrimers [18]. Thus it is reasonable to think that maltose dendrimers interacting with Aβ may form hybrid fibrils, shifting the balance between oligomeric and fibrillar forms of Aβ toward less toxic hybrid products.
\nEffect of G4 histidine-maltose PPI dendrimers on the fibrillization of Aβ. (A) Aggregation of 20 μM Aβ(1–40) in the absence (red) and the presence of histidine-maltose PPI dendrimers. (Magenta) 20 μM Aβ(1–40) in the presence of dendrimers at dendrimer/peptide ratio = 0.1, (blue) 20 μM Aβ(1–40) in the presence of dendrimers at dendrimer/peptide ratio = 1. (B) Aggregation of 25 μm Aβ(1–42) in the absence (red) and in the presence of histidine-maltose PPI dendrimers. (Magenta) 25 μM Aβ(1–42) in the presence of dendrimers at dendrimer/peptide ratio = 0.1, (blue) 25 μM Aβ(1–42) in the presence of dendrimers at dendrimer/peptide ratio = 1. The temperature was 37°C, the pH was set to 7.4, and the concentration of ThT was 6 μM (adapted with permission from [
Dendrimers’ intrinsic toxicity is an important issue in relation to their potential biological applications [37]. It was observed that unmodified PPI dendrimers have high intrinsic toxicity for cells [38, 39]. It was hypothesized that this toxicity could be related to the dendrimer capacity of establishing strong interactions of electrostatic nature [40]. It has been demonstrated that dendrimers with a surface decorated by polysaccharides, such as maltose or maltotriose, confer less toxicity [41, 42]. The charge of the dendrimer covered by polysaccharides is close to neutral; thus the interaction of dendrimer with other biomolecules is driven by hydrogen bonds, which is less strong; therefore, dendrimers covered by polysaccharides are less toxic [38, 39, 41].
\nIn collaborations between the research groups of Dietmar Appelhans (Leibniz Institute of Polymer Research, Dresden, Germany), Josep Cladera (Autonomous University of Barcelona, Spain), and Isidro Ferrer in Barcelona (University of Barcelona, Spain), it has been shown that distinct PPI dendrimers with electroneutral maltose shell, with cationic maltose or maltotriose shell, were tested against amyloid toxicity in vivo and in vitro. The evaluation of the toxicity of Aβ in the presence of PPI maltose dendrimers showed that the dendrimers could significantly reduce the Aβ toxicity compared to Aβ alone [28].
\nInterestingly, only the electroneutral maltose dendrimers were able to reduce the toxicity of Alzheimer’s disease brain extracts in cultured SH-SY5Y neuroblastoma cells [28]. Moreover, maltose PPI dendrimers with electroneutral or cationic surface penetrated the cytoplasm of cultured cells. Additionally, they penetrated inside the brain when administered to AD transgenic mice intranasally [28]. These PPI maltose dendrimers were able to modify amyloid plaque load in the brains of AD transgenic animals, showing anti-amyloid potential for in vivo applications. However, the studied maltose PPI dendrimers could not reverse memory impairment in APP/PS1 mice following chronic administration. Strikingly, cationic maltose dendrimers were neurotoxic in vivo and caused cognitive decline in non-transgenic mice [28]. Taken together, these results suggest that maltose PPI dendrimers require further optimization of biocompatibility.
\nAs it has been mentioned at the beginning of the chapter, Alzheimer’s disease is a fatal neurodegenerative disorder. AD is characterized by a decade-long presymptomatic phase, and it is during the presymptomatic phase, before synaptic damage and neuronal loss, that therapies are most likely to be effective [43]. Thus, a preventive treatment which could protect synapses and reduce the neurotoxicity of Aβ oligomers is one such strategy. Such successful drug candidates for AD treatment have to possess both anti-amyloidogenic and neuroprotective properties. Therefore, a modification of maltose dendrimers with a molecule with neuroprotective characteristics was the next logical step in search of the new drug candidate for the treatment of AD.
\nTo further improve the pharmacological properties of maltose PPI dendrimers, it was decided to modify PPI dendrimers of the fourth generation with maltose and histidine. Maltose was used due to anti-amyloidogenic properties; histidine was added due to several reasons: it is selectively transported through the BBB [44]. Histidine has chelating properties for Cu2+ ions [45]. Thus these properties were considered to be important since Cu ion dyshomeostasis may play a detrimental role in AD progression [46], and importantly, histidine has been shown to have some neuroprotective capacity [47]. After the modification, G4 PPI dendrimers modified with maltose and histidine were supposed to possess both anti-amyloid and neuroprotective properties simultaneously.
\nIn vitro evaluations demonstrated that histidine-maltose PPI dendrimers could interact with Aβ. As maltose PPI dendrimers, G4 histidine-maltose PPI dendrimers did not prevent fibril formation but clump Aβ fibrils (Figure 5). Importantly, small oligomeric aggregates were not present in the studied suspensions in the presence of the dendrimers. Interestingly, the intensity of ThT was significantly decreased following the aggregation of Aβ probably due to the competition of the dendrimers with ThT for binding to Aβ(1–40) or due to change of structure, resulting in lower ThT fluorescence quantum yield [48, 49]. To test if G4 histidine-maltose PPI dendrimers could reduce the neurotoxicity of Aβ, primary neurons derived from wild-type mouse were treated with 1 μM Aβ(1–42) in the presence of the dendrimers at the ratio 1 to 1. As it was demonstrated by cell viability assay, histidine-maltose PPI dendrimers significantly reduced the neurotoxicity of soluble Aβ oligomers [22]. Figure 6 shows the neuronal viability in the presence of the dendrimers and Aβ(1–42) oligomers as assessed by a lactate dehydrogenase (LDH) activity assay. 1 μM G4 histidine-maltose PPI dendrimers were added to primary neurons and incubated 24 h before the assay; as it was documented, the dendrimers alone were not toxic to the neurons. 1 μM recombinant Aβ(1–42) monomers, oligomers, and fibrils were added to primary neurons and incubated 1 h at 37°C in the presence and the absence of dendrimers. The results demonstrate that G4 histidine-maltose PPI dendrimers significantly reduced the toxicity of Aβ(1–42) for primary neurons.
\nEffect of G4 histidine-maltose PPI dendrimers on Aβ morphology. (A) Electron microscopy micrographs of 25 μM Aβ(1–40) incubated at pH 7.4 for 24 h. (B) 25 μM Aβ(1–40) incubated at pH 7.4 in the presence of G4 histidine-maltose PPI dendrimers at the ratio 1 to 1. (C) Aβ(1–42) incubated at pH 7.4 for 24 h. (D) Aβ(1–42) incubated in the presence of G4 histidine-maltose PPI dendrimers (clumped fibrils). Scale bar is 200 nm.
G4 histidine-maltose PPI dendrimers reduce the toxicity of Aβ oligomers for cultured primary neurons. (A) ThT fluorescence variation was used to monitor aggregation of 10 μM Aβ(1–42) in PBS at 37°C (black line); red line corresponds to ThT alone. The arrows indicate the time when aliquots of Aβ(1–42) were taken for neuronal viability assay. Aβ-M, a monomeric form of Aβ(1–42); Aβ-O, an oligomeric form of Aβ(1–42); Aβ-F, mature fibrils of Aβ(1–42); (B) 1 μM of G4 histidine-maltose PPI dendrimers were added to primary neurons and incubated 24 h before a cell viability assay. Cell viability was assessed by a lactate dehydrogenase activity assay. For the assay, 1 μM Aβ(1–42) of monomers, oligomers, and fibrils were added to wild-type primary neurons and incubated 1 h at 37°C. statistics: one-way ANOVA followed by Tukey’s post hoc test; data are expressed as mean ± SD. Primary neurons were derived from the brains of wild-type mouse embryos and cultured for 19 days. The experiment was performed in triplicate, one embryo per replica (adapted with permission from [
In vivo evaluations demonstrated that chronic treatment with histidine-maltose PPI dendrimers of APP/PS1 mice prevented AD-related memory impairment [22]. Figure 7 shows the results of the memory test after the treatment. APP/PS1 mice harbor two human genes: APP with the KM670/671NL, the Swedish mutation, and PSEN1 with the L166P mutation [50]. In APP/PS1 mice, human Aβ increases with age, but Aβ42 is preferentially generated over Aβ40, and the expression of the human APP transgene is approximately 3-fold higher than the endogenous murine APP [51]. For the treatment, APP/PS1 and wild-type mice were randomly divided into four groups, two groups (transgenic and wild type) were treated intranasally with histidine-maltose PPI dendrimers, and two groups (transgenic and wild type) were given intranasally phosphate saline. Administration lasted 3 months until animals reached the age of 6 months, the age when the first cognitive decline is detected [52]. Memory evaluation tests were performed at the end of treatment using two object recognition tests in a VmazeR as described [52].
\nG4 histidine-maltose PPI dendrimers can protect memory in vivo. Memory performance in the V-maze shows significant improvement after preventive treatment with histidine-maltose PPI dendrimers. Treatment procedure: at the age of 3 months, animals were randomly divided into four groups; two groups control and APP/PS1 mice were given intranasally 5 μL of PBS, and two groups received intranasally 5 μg/day of G4 histidine-maltose PPI dendrimers (dendrimers). Treatment lasted 3 months until animals reached the age of 6 months when APP/PS1 mice display cognitive impairment [
To understand a possible mechanism behind the memory rescue, the levels of pre- and postsynaptic markers in the brain of treated APP/PS1 mice were evaluated by Western blotting. Pre- and postsynaptic markers, such as drebrin and synaptophysin, play a crucial role in the synaptic plasticity and are downregulated in AD [53, 54]. Loss of synaptophysin correlates with cognitive impairments in AD patients and AD transgenic models [54, 55]; Psd95 knockout animals have impaired basal synaptic transmission and learning deficit [56]; transgenic animals lacking synaptophysin have reduced novel object recognition [57]. Importantly, it has been shown that loss of synaptophysin immunoreactivity precedes amyloid plaque formation [58, 59]. Preventive treatment of AD transgenic mice with G4 histidine-maltose PPI dendrimers prevented a decrease in synaptic proteins compared to PBS-treated mice [22].
\nIn contrast, G4 histidine-maltose PPI dendrimers did not change the level of these synaptic proteins in WT mice, indicating that, most likely, the level of their mRNA expression was not affected [22]. Thus it is reasonable to think that the increased levels of pre- and postsynaptic proteins are more likely an effect of reduced synaptic loss in the treated AD transgenic animals (Figure 8). Thus a possible mechanism of memory protection in APP/PS1 could be the synapses were shielded by the dendrimers from toxic Aβ oligomers or the toxicity of Aβ oligomers were inactivated in the presence of the dendrimers.
\nG4 histidine-maltose PPI dendrimers protect synapses in vivo. (A) Synapse is a junction between two neurons, which consist of pre- and postsynaptic terminals characterized by specific pre- and postsynaptic proteins. Synaptophysin was used to assess presynapse, while drebrin was used to evaluate postsynapse. Brain tissue homogenates of control mice and mice treated with G4 histidine-maltose PPI dendrimers (dendrimers) were analyzed using Western blotting; β-actin was used for protein normalization. Statistics: Student’s t-test (N is the number of animals per group, Western blotting was done in triplicate). Data are expressed as mean ± SD.
Dendrimers, which represent a type of 3D polymers, have been in the spotlight for three decades in biomedical and pharmaceutical research, and their chemistry and synthesis are continuously progressing by efforts from many research groups and companies. Although there are still many unclear problems in AD, in this chapter, functionalization of dendrimers dedicated to the prevention of memory decline in AD pathogenesis has been discussed. Based on the reviewed literature, PPI dendrimers have been shown to be useful in the way of the surface functionalization, which tuned their biochemical properties. Strikingly, the effect of the surface functionalization with histidine and maltose magnified exponentially neuroprotective properties of PPI dendrimers, resulting in an unprecedented outcome, such as memory protection in AD transgenic animals.
\nIn this chapter, I have analyzed the functionalization of PPI dendrimers, which tuned the intrinsic properties of PPI dendrimers and converted them into a multifunctional drug candidate against Alzheimer’s disease. Modification of the dendrimer surface with maltose allowed dendrimers successfully to interfere with Aβ(1–42) by forming nontoxic hybrid glycofibrils. Modification of the dendrimer surface with histidine improved the ability of the dendrimers to cross the blood–brain barrier and resulted in synaptic protection. By reducing the level of soluble amyloid oligomers, on the one hand, and conferring synapse protection, on the other hand, the dendrimers were given multifunctionality against main features of AD, synaptic loss, and aggregation of Aβ. These observations, coming out of the studies on the interaction of dendrimers with amyloid peptides [18, 22, 28, 32, 42], carried out in vitro and in vivo, point toward a possible use of dendrimers (in particular functionalization of PPI dendrimers with histidine and maltose) as a multifunctional drug candidate against Alzheimer’s disease.
\nHowever, to find a successful drug against AD, other modifications of histidine-maltose PPI dendrimers might be required. For example, the ability to cross the blood-brain barrier, cell wall penetration, distribution in the specific tissue, and biodegradation could be tuned for a particular dendrimer application.
\nI acknowledge Dr. Dietmar Appelhans (Leibniz Institute of Polymer Research Dresden, Dresden, Germany) for the generation of histidine-maltose PPI dendrimers, collaboration, and valuable discussions.
\nThe work is supported by MultiPark (Lund University), Vinnova, Swedish Research Council grants.
\nI thank Dr. Stefan Broselid for fruitful discussions and editorial help.
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Pharmacogenetics for cancer treatment is very significant, as cancer therapies exhibit severe systemic toxicity and unpredictable efficacy. There is presence of genetic polymorphisms in the genes which code for the metabolic enzymes and cellular targets for the majority of chemotherapy agents, but to predict the outcome of chemotherapy in patients is not currently possible for most treatments. A greater understanding of the genetic determinants of drug response can revolutionize the use of many medications. By identifying the patients at risk for severe toxicity, or those likely to benefit from a particular treatment, individualized cancer therapy can be achieved for most cancer patients. The prediction of cancer treatment outcome based on gene polymorphisms is becoming possible for many classes of chemotherapy agents, and the most clinically significant examples of chemotherapy agents are discussed in the chapter. 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Although molecular medicine for disease intervention is still in its infancy, however, significant research works and successful trials in short span of time have made it broadly accepted among the scientific community. This chapter identifies different molecular medicine approaches for dealing with parasites that have been coming up on the horizon with the new technological advances in bioinformatics and in the field of omics. With the better understanding of the genomics, molecular medicine field has not only raised hopes to deal with parasitic infections but also accelerated the development of personalized medicine. This will provide a targeted approach for identifying the druggable targets and their pathophysiological importance for disease intervention.",book:{id:"9569",slug:"methods-in-molecular-medicine",title:"Methods in Molecular Medicine",fullTitle:"Methods in Molecular Medicine"},signatures:"Bhawana Singh",authors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}]}],onlineFirstChaptersFilter:{topicId:"981",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:36,paginationItems:[{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",doi:"10.5772/intechopen.105008",signatures:"Hailian Shen",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},overviewPagePublishedBooks:{paginationCount:32,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. 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Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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