Some standard enzyme inhibitors commonly used.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\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:"2360",leadTitle:null,fullTitle:"Livestock Production",title:"Livestock Production",subtitle:null,reviewType:"peer-reviewed",abstract:"Innumerable publications on livestock production are available in the world market. 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\r\n\tVirtual Instrumentation revolutionized the engineer's and scientists’ activities in the field of measurements, monitoring, and testing. The main programing environment used for virtual instrument implementation in LabVIEW was developed by NI company. A very important aspect of education and engineering development is to use the right tool. In the current development, PCs and embedded systems are on a large scale use. Therefore, the programming of these could be a challenge for non-programming specialists. LabVIEW offers a solution for developing and implementing complex applications even for non-programming specialists. The LabVIEW libraries and add-ons offered by NI or the community allow educators and engineers to cover domains that otherwise would not be tangible for them. This book aims to collect original works and reviews concerning subjects such as correct technique programming approaches, simulation and modeling, systems control, remote control, IoT and IIoT, renewable energy, artificial intelligence, and combining LabVIEW with other programming languages.
\r\n\t
Due to their essential catalytic role in several physiological processes, enzymes are considered to be one of the most attractive targets for drug intervention in human diseases [1]. Indeed, the therapy of some important human aliments, namely hypertension, metabolic disorders, inflammatory diseases and neurodegenerative diseases, includes the use of enzyme inhibitors. Nevertheless, some of the inhibitors currently in use (Table 1) are reported to have side effects, including hepatotoxicity, gastrointestinal disturbances and diarrhea [2–4]. Consequently, there is a great interest in finding new effective natural inhibitors without undesirable effects.
Diseases | Enzyme | Main standard inibitor(s) |
Hypertension | Angiotensin-converting enzyme | Aptopril, benazepril, enlapril |
Diabetes | α-Amylase and α-glucosidase | Acarbose |
Obesity | Pancreatic lipase | Orlistat |
Alzheimer’s diseases | Cholinesterases | Tacrine, donepezil, rivastigmine, galantamine |
Inflammation | Cyclooxygenases and 5-lipoxygenase | Indomethacin |
Skin hyperpigmentation | Tyrosinase | Kojic acid |
Some standard enzyme inhibitors commonly used.
The discovery of enzyme inhibitors to be used in human therapeutics is an active and actual area of research. Several studies provided evidence about the beneficial effects of phenolic compounds in human health due to their wide range of biological properties, namely antioxidant, anticancer, and antimicrobial [5]. The biological actions of phenolic compounds involve different mechanisms including the interaction with enzymes [6]. In the last years, a great number of reports were published describing the inhibitory potential of phenolic compounds against human enzymes. The present chapter aims to systematize the information about the enzyme inhibitory properties of phenolic compounds against key enzymes associated to several human diseases, namely angiotensin I-converting enzyme, α-amylase, α-glucosidase, lipase, cholinesterases, cyclooxygenases (COXs), 5-lipoxygenase (5-LOX) and tyrosinase.
Chronic diseases or non-communicable diseases are adverse health conditions of long duration and, generally, also of slow progression, causing 63% of all deaths worldwide (36 million out 57 million global deaths) [7, 8]. These diseases can be classified into five main groups: cardiovascular diseases; cancer; chronic respiratory diseases, such as chronic obstructed pulmonary disease and asthma; diabetes; and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. Hypertension is one of the major risk factors for cardiovascular diseases and is estimated to affect one-third of the Western population [9]. Obesity is also considered a global epidemic problem and is associated with multiple chronic diseases [10]. Overproduction of oxidants and chronic inflammation is responsible for the pathogenesis of many chronic diseases, and experimental and epidemiological studies demonstrated that plant antioxidants play an important role in the prevention and treatment of these diseases. Plant-derived antioxidants, particularly phenolic compounds, can reduce the oxidative stress in the body maintaining, a balance between oxidants and antioxidants due to their reducing, free radical scavenging or metal chelating properties [8]. Phenolic compounds can easily donate hydrogen from hydroxyl groups positioned along the aromatic ring to terminate free radical oxidation of lipids or other biomolecules, and the aromatic phenolic ring can stabilize and delocalize the unpaired electron within its aromatic ring [11].
More than 8000 different structures of phenolics have been identified up to now [12]. Phenolics may be classified into different groups depending upon the number of phenol rings and the structural elements that bind these rings to one another [13]. The main groups of phenolic compounds are flavonoids, phenolic acids, tannins, stilbenes and lignans [13]. Flavonoids are probably the most important group of phenolic compounds. These are molecules of low molecular weight that have a common C6–C3–C6 structure consisting of two aromatic rings (A and B) linked through a three carbon chain, usually organized as an oxygenated heterocycle (ring C) (Figure 1) [6]. Flavonoids can be characterized as flavanones, flavones, flavonols, isoflavones, flavanols (essentially, flavan-3-ols) and anthocyanidins. This classification depends on the degree of unsaturation and oxidation of the oxygenated heterocycle [6]. Many authors demonstrated that the position and number of substituents in the flavonoid basic structure significantly affect the biological function [6, 14].
Chemical structure of selected flavonoids. Adapted from Fraga et al. [
The biological action of phenolic compounds involves different mechanisms including nonspecific and specific mechanisms [6]. Nonspecific mechanisms are for instance the free radical scavenging and metal sequestration capacity of phenolic compounds and their interactions with membranes. On the other hand, specific mechanisms include the interaction of phenolics with enzymes, with transcription factors or with receptors. The complexity of some diseases leads to the recent search for alternative therapeutic strategies based on combined therapy protocols and multifunctional compounds. Thus, phenolic compounds, showing a wide range of biological effects through different mechanisms, have a great potential to be used in the prevention and treatment of several human diseases (Figure 2).
Snapshot of some of the health benefits of phenolic compounds.
Enzyme inhibitors can have many applications in pharmaceutical, environment and biochemical industries, having a great impact on healthcare and medical sector. The control of some important human diseases includes the use of enzyme inhibitors which represent a great part of the drugs in clinical use. Specific enzyme inhibition will remain a major focus of pharmaceutical research for the foreseeable future [1]. Enzymes are protein molecules acting as catalyst in biological systems. Enzymes specificity assures high coordination and harmonious interplay among different metabolic activities essential to sustain life. The enzyme activity depends on numerous factors, for example, the most important the enzyme concentration, the amount of specific enzyme substrate, the electrochemical reaction of medium for enzyme activity (pH) and the presence of activators or inhibitors.
Enzyme inhibitors prevent enzymes from their catalytic function by interfering with any step in the catalytic cycle. They are low molecular weight compounds that in small quantity can reduce or completely inhibit the enzyme activity [15]. Some human enzyme inhibitors, such as antithrombin and antitrypsin, control the enzyme activity in the body, and under physiological conditions, they guarantee their action. Among natural enzyme inhibitors, there are intermediary products produced during some metabolic pathways. The inhibition of products is a restricted way of control or modulation of substrate flux through the pathway. If enzymes are sensitive to product inhibition, the output of end product of the pathway will be suppressed [16].
An inhibitor can modify one amino acid or several side chain(s) required in enzyme catalytic activity. To protect enzyme catalytic site from any change, ligand binds with critical side chain in enzyme. Enzyme inhibitors are conceptually classified as specific and nonspecific. Inhibitors can reduce or completely inhibit the enzyme catalytic activity reversibly or irreversibly. Irreversible inhibitors usually change the enzyme chemically. Reversible inhibitors bind non-covalently to produce different types of inhibition, depending on whether these inhibitors bind the enzyme, the enzyme-substrate complex, or both. Most drugs that function through enzyme inhibition interact with their target enzyme through simple, reversible binding mechanisms [1]. Reversible inhibitors can be classified into competitive, noncompetitive or uncompetitive (Figure 3). In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time; therefore, the competitive inhibitor competes with the substrate for the active site. A noncompetitive inhibitor binds equally well to both free enzyme and the enzyme-substrate complex. An uncompetitive inhibitor binds exclusively to the enzyme-substrate complex yielding an inactive enzyme-substrate-inhibitor complex.
Scheme representative of the three major forms of reversible inhibitor interactions with enzymes: (1) competitive inhibition; (2) noncompetitive inhibition; (3) uncompetitive inhibition. S: Substrate; E: free enzyme (E); ES: enzyme-subtract complex; I: inhibitor; ESI: enzyme-subtract-inhibitor complex. Adapted from Copeland [
The use of plant-based enzyme inhibitors is encouraged nowadays because there is concern about the critical side effects of synthetic pharmaceutical agents. In the following sections, the enzyme inhibitory properties of phenolic compounds are reviewed. Investigations have been mainly focused in angiotensin I-converting enzyme, α-amylase and α-glucosidase, lipase, cholinesterases, proinflammatory enzymes (COXs and 5-LOX) and tyrosinase, which are linked with hypertension, type II diabetes, obesity, Alzheimer’s diseases, inflammation and skin hyperpigmentation, respectively (Table 2). These were selected to be included in this chapter although there are evidences of the inhibitory properties of phenolic compounds against other enzymes like monoamine oxidase and catechol-
Diseases | Enzyme | Compound(s) | Important references |
Hypertension | Angiotensin-converting enzyme | Flavonoids | [14] |
Tannic acid | [19] | ||
Anthocyanins | [27] | ||
Proanthocyanidins | [28] | ||
Diabetes | α-Amylase and α-glucosidase | Flavonoids | [37, 39, 40] |
Obesity | Pancreatic lipase | Flavonoids, phenolic acids | [47] |
Alzheimer’s diseases | Cholinesterases | Flavonoids | [53, 54] |
Coumarins | [59] | ||
Inflammation | Cyclooxygenases and 5-lipoxygenase | Flavonoids | [62, 64–67] |
Stilbenes | [61, 62] | ||
Skin hyperpigmentation | Tyrosinas | Flavonoids | [71, 73] |
Stilbenes | [72, 74, 75] | ||
Chalcones | [72] |
Main phenolic compounds described as inhibitors of enzymes linked with human ailments.
Hypertension is a common and often progressive disorder that poses a major risk for cardiovascular diseases and related complications [18]. Hypertension is an important and increasing public health problem worldwide, and some data indicate that about one-quarter of the adult population suffers from this condition [19]. Inhibition of angiotensin-converting enzyme (ACE) is considered to be a target for discovery of lead antihypertensive agents and an important therapeutic approach in the treatment of high blood pressure [20]. ACE catalyzes the conversion of the precursor angiotensin I into angiotensin II, a peptide responsible for triggering vasoconstrictive effects, and it degrades bradykinin, a potent vasodilator [21, 22]. Some of the widely used ACE inhibitors such as aptopril, benazepril, enlapril and other [23] have revealed certain limitations like susceptibility to proteolytic degradation leading to side effects. Therefore, research has been conducted to find new ACE inhibitors from natural sources particularly from plant origin. Many investigations indicate that polyphenol-rich food is effective in the protection and treatment of hypertension namely via ACE inhibition [24]. In a recent review, Patten et al. [25] described 74 families of plants that exhibited significant ACE inhibitory activity. Also, Field and Newton [26] have shown that cocoa polyphenols are bioavailable molecules that induce an antihypertensive response including through ACE inhibition.
Guerrero et al. [14] evaluated the ability of 17 flavonoids belonging to five structural subtypes to inhibit ACE and showed that the highest activity was obtained for luteolin. Results from these authors allow concluding that the combination of substructures on the flavonoid skeleton that increase ACE activity is made up of the catechol group in the B-ring, the double bond between C2 and C3 at the C-ring and the cetone group in C4 at the C-ring. Al Shukor et al. [19] investigated the ACE-inhibitory capacity of 22 phenolic compounds belonging to different classes and subclasses. Among analyzed compounds, tannic acid exhibited the highest ACE-inhibitory activity. Results indicated that the number of hydroxyl groups on the benzene ring plays an important role for activity of phenolic compounds and that substitution of hydroxyl groups by methoxy groups decreased activity. Furthermore, phenolic acids and flavonoids inhibit ACE via interaction with the zinc ion, and this interaction is stabilized by other interactions with amino acids in the active site. Resveratrol and pyrogallol may inhibit ACE via interactions with amino acids at the active site blocking the catalytic activity of ACE [19].
Several studies suggest anthocyanins as important ACE inhibitors. Ojeda et al. [27] demonstrated the ACE-inhibitory capacity of the anthocyanins delphinidin-3-
Disorders of carbohydrate uptake may cause severe health problems such as diabetes, obesity and oral diseases [29]. Diabetes mellitus (DM) is one of the most serious and chronic diseases and can be attributed to hyperglycaemia, a condition characterized by an excessive concentration of glucose circulating in the blood. Two types of DM are known, type I that is characterized by insufficient insulin production and type II that results from ineffectiveness of insulin [30]. Type II DM accounts for approximately 90% of diabetes cases worldwide and is attributed to greater prevalence of sedentary lifestyle, unhealthy diet and rise of obesity within modern society as well as an increasing number of elderly populations [31, 32]. Type II DM has become a serious medical concern worldwide and is frequently correlated with many complications such as cardiovascular diseases, hypertension, kidney failure, blindness, and neurological complications [33].
One therapeutic approach for treating DM type II is to decrease the postprandial glucose levels, which could be done by retarding the absorption of glucose through the inhibition of the carbohydrates-hydrolyzing enzymes, α-amylase and α-glucosidase, in the digestive tract. These enzymes are responsible for the breakdown of oligosaccharides and disaccharides into monosaccharides suitable for absorption. Inhibitors of these enzymes delay the rate of glucose absorption by preventing carbohydrate digestion and consequently blunting the postprandial plasma glucose rise [34]. The use of synthetic agents as acarbose is an important clinical strategy for controlling postprandial glycemia [35]. Acarbose reduces blood glucose levels and is approved by Food and Drug Administration (FDA); however, it causes critical side effects, such as liver disorders [4], and its use is now restricted [36]. To avoid or decrease the adverse effects of currently used synthetic inhibitors, it is necessary to employ naturally occurring alternatives. In the last years, several reviews have been published focusing on the antidiabetic potential of natural products including on the inhibitory properties of phenolic compounds against carbohydrates-hydrolyzing enzymes [29, 30, 37, 38]. Phenolic compounds have been receiving much attention for controlling the digestibility of starch [30], and flavonoids are widely studied as α-amylase inhibitors [37]. Tadera et al. [39] tested several flavonoid compounds for their inhibitory activity against α-amylase and showed that, in general, the potency of inhibition is correlated with the number of hydroxyl groups on the B ring of the flavonoid scaffold. The structural requirements for the inhibition of human salivary α-amylase by 19 flavonoids were studied by Lo Piparo et al. [40]. Author’s findings demonstrated that the flavonols and flavones enzyme inhibitory capacity depend on hydrogen bonds between the hydroxyl groups of the polyphenol ligands and the catalytic residues of the binding site and formation of a conjugated α-system that stabilizes the interaction with the active site. Recently, Xiao et al. [37] revised the structure-activity relationship of polyphenols inhibiting α-amylase and concluded that the hydroxylation galloylation of flavonoids, including catechins, improved the inhibitory effects against α-amylase. Moreover, these authors also observed that the glycosylation of the hydroxyl group, methylation, methoxylation and the hydrogenation of the C2-C3 double bond on flavonoids decreased the inhibition of the enzyme.
There are also some reports describing the inhibitory properties of other classes of phenolic compounds, like hydroxycinnamic acids and tannins, against α-amylase and α-glucosidase; however, overall they are less effective than flavonoids [29, 37].
Phenolic compounds, in particular flavonoids, may provide a protective effect against hyperglycemia-induced chronic diseases through a dual protection: inhibition of starch digestion and antioxidant effect. The co-application of phenolics with synthetic enzyme inhibitors for controlling prosprandial glycemia may reduce the effective dose of synthetic inhibitors required [30].
Obesity is considered a global epidemic problem by the World Health Organization (WHO) and is recognized as the main life style disorder in developing countries, being termed as the “New World Syndrome.” It is associated with multiple chronic diseases and disabilities such as dyslipidemia, fatty liver disease, osteoarthritis, hypertension, obstructive sleep apnea, gallstones, type II diabetes, reproductive and gastrointestinal cancers, coronary artery disease, heart failure and stroke [10, 41, 42].
The methods used to reduce body weight include diet, exercise, drug therapy, bariatric surgery or combinations of several of these methods. Currently, orlistat (Xenical) is the only drug approved by FDA for long-term treatment of obesity [43, 44]. Orlistat reduces intestinal triglyceride absorption through inhibition of pancreatic lipase. Its long-term administration is associated with a small but statistically significant weight loss of about 3% more than diet alone in overweight and obese people [45]. Moreover, it can also decrease blood pressure, prohibit the onset of DM type II and improve oral glucose tolerance [44]. However, some adverse gastrointestinal effects of orlistat have been reported as steathorrhea, bloating, oily spotting, fecal urgency and fecal incontinence, as well as hepatic adverse effects [2]. Thus, there has been an increase interest in the search for new natural substances that show potent inhibitory activity against pancreatic lipase with fewer side effects. As a result, many plant extracts and compounds have been screened for their capacity to inhibit pancreatic lipase [44, 46, 47]. Among plant compounds, proteins, polysaccharides, saponins, triterpenes and phenolic compounds have shown capacity to inhibit this enzyme [46]. Phenolic compounds have some potential efficacy for preventing obesity by inhibiting the activity of enzymes related to fat metabolism as pancreatic lipase, lipoprotein lipase and glycerophosphate dehydrogenase [48]. Examples of compounds with pancreatic lipase inhibitory capacity are the flavonoid hesperidin from the peels of
Alzheimer’s disease (AD), the most common form of dementia, is a progressive age-related neurodegenerative disorder. AD rates are predicted to increase enormously, especially in developing regions, considering the accelerated aging of human society and the increase in life expectancy worldwide. Although the exact pathogenesis of AD still remains to be fully elucidated, it is currently considered to be a multifactorial disease. In the early 1970s, postmortem studies revealed that choline uptake and acetylcholine release are reduced in the brains of AD patients being these reductions associated with substantial presynaptic cholinergic deficits [50]. This led to the establishment of the “cholinergic-deficit hypothesis,” which posits that the impairment in the cholinergic function is of critical importance in AD especially in the brain areas dealing with learning, memory, behavior and emotional responses that include the neocortex and the hippocampus. The levels of acetylcholine, a neurotransmitter responsible for the conduction of electrical impulses from one nerve cell to another nerve cell, are decreased due to its rapid hydrolysis by acetylcholinesterase (AChE) enzyme [3, 50]. Butyrylcholinesterase (BChE) is an enzyme closely related to AChE and serves as a co-regulator of cholinergic neurotransmission by hydrolyzing acetylcholine [51]. Some studies have shown an increased BChE activity in the most affected areas of the brain during the development of AD. The inhibition of both AChE and BChE has been documented as critical targets for the management of AD by an increase in the availability of acetylcholine and decrease in the Aβ deposition. However, the brain region contains a small quantity of BChE since it is mostly localized in the peripheral tissues. Therefore, the potential advantage of selective inhibition of AChE over BChE may include lesser degree of associated side effects due to peripheral inhibition of cholinesterase enzyme [52]. The first drug developed for AD based on the cholinergic-deficit hypothesis was tacrine that was approved for the treatment of cognitive loss in patients with AD by the FDA in 1993 [3]. Later, other cholinesterase inhibitors, like donepezil (1996), rivastigmine (2000) and galantamine (2001), have been approved and used for the management of AD [3, 52]. Due to the limited efficacy and gastrointestinal side effects of these drugs, such as nausea and diarrhea, there has been a continuous effort to find more effective cholinesterase inhibitors to be used to prolong and improve the life of the AD patients [3]. In this sense, plant extracts and compounds have been investigated for their role in prevention and treatment of AD including as cholinesterase inhibitors. Several investigations described the anticholinesterase effects of many naturally occurring flavonoids and newly synthesized flavonoids analogues. Uriarte-Pueyo and Calvo [53] reviewed the acetylcholinesterase inhibitory capacity of 128 flavonoids and conclude that flavones and isoflavones are the compounds with higher activity, proving that the carbonyl group at C4 seems to be important in this activity. Later on, Anand and Singh [54] discussed the data on the effects of flavonoids in various enzyme targets that play an important role in the pathogenesis of AD. Some conclusions arising are that isoflavone analogues demonstrate high AChE inhibitory activity, as compared to chalcone, flavones and flavanone analogues, suggesting that the nature of flavonoid moiety affects AChE inhibition in a great extent. Moreover, different moieties capable of interacting with catalytic site of AChE, including benzyl piperidine, piperidine, pyrrolidine, have been linked to paraposition of ring B of flavonoid scaffold using appropriate spacer to obtain dual-binding AChE inhibitors. Flavonoids may be attractive lead compounds for the development of effective and safe anti-AD drugs by modulating the enzyme targets in the disease [54].
Other compounds with potent AChE inhibitory activity are coumarins [55], and similar to flavonoids, several coumarins analogues have been synthesized, and their enzyme inhibitory capacity evaluated. Data on the inhibitory effects of coumarins against cholinesterases have been reviewed by several authors [56–58]. Various coumarins obtained from plants particularly from the
Chemical structure of some coumarins with cholinesterase inhibitory capacity.
Numerous studies showed that phenolic compounds not only exhibit cholinesterase inhibitory capacity as potent antioxidant and anti-inflammatory properties, acting to scavenge radicals and regulate inflammatory responses; moreover, some of these compounds readily cross the blood-brain barrier to act on specific targets that have been implicated in the pathogenesis of AD.
Several diseases such as diabetes, obesity, cancer, osteoarthritis, atherosclerosis and Crohn’s disease are associated with chronic inflammation. The mechanisms of inflammation involve a series of events in which the metabolism of arachidonic acid plays an important role [61] COX-1 and COX-2 enzymes catalyze the conversion of arachidonic acid to prostanoids. The second pharmacologically relevant metabolic pathway of arachidonic acid is mediated by 5-LOX. This enzyme is involved in the biosynthesis of inflammatory mediators named leukotrienes. COXs and LPXs are considered proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later, the development of atherosclerosis [62]. Both COXs and 5-LOX have received considerable attention because they are putative targets for cancer prevention. Nonsteroidal and steroidal anti-inflammatory drugs exert their action by inhibiting these proinflammatory enzymes through different mechanisms [63]. The nonsteroidal and steroidal anti-inflammatory drugs currently in use effectively manage the acute inflammatory reaction; however, in chronic inflammatory states, the long-term treatment with these drugs is followed by severe adverse effects. This justifies the search for new and safe anti-inflammatory agents being plant compounds good candidates. Recently, there has been interest in the antiinflammatory/immunomodulatory potential of flavonoids including their capacity to inhibit the activity of proinflammatory enzymes [64–66]. Li et al. [66] demonstrated the anti-inflammatory activity of the flavonoid baicalin. This compound inhibits COX-1, COX-2 and 5-LOX activities, decreases production of proinflammatory eicosanoids and attenuates edema in an
Stilbenes are another important group of plant compounds with anti-inflammatory properties. Kutil et al. [61] recently demonstrated that several natural stilbenes are potent inhibitors of proinflammatory enzymes and not only the most extensively studied compound of this group, resveratrol (3,5,4′-trihydroxy-trans-stilbene) found in red wine. The same group [62] evaluated the inhibitory potential of several wines and 33 phenolic compounds commonly occurring in wine against COX-1, COX-2, and 5-LOX. Authors observed that red wines were potent inhibitors of all three tested enzymes but the results obtained with isolated compounds could not fully explain the overall activities of the wine. Although trans-resveratrol considerably inhibits both COX-1 and COX-2, the activity of this compound alone could not be responsible for the overall inhibitory activity. In addition, results also showed that piceatannol, luteolin, quercetin, and myricetin were potent inhibitors of 5-LOX, but considering the ratio between their IC50 values and their concentration in wine only piceatannol could substantially contribute to the overall activity of red wines. Authors hypothesize that wine proanthocyanidins could also contribute to its overall potential since their inhibitory capacity against these enzymes was previously described.
The color of mammalian skin is mainly determined by the degree and distribution of melanin pigmentation. Melanin plays an important role in protecting skin from ultraviolet UV damage; however, overproduction of melanin poses not only an esthetic but also a dermatological problem. Indeed, some dermatological disorders, such as melasma and age spots, result in the accumulation of an excessive level of epidermal pigmentation [68].
Melanin is formed by several oxidative reactions which involve tyrosine and tyrosinase [69]. Tyrosinase catalyses three reactions in the biosynthetic pathway of melanin in melanocytes: the hydroxylation of tyrosine to L-DOPA and its oxidation to dopaquinone. Following a series of oxidoreduction reactions, the intermediate dihydroxyindole DHI and dihydroxyindole carboxylic acid are produced and polymerized to form melanins [70]. The inhibition of tyrosinase is one of the major strategies used to treat hyperpigmentation; however, concerns over the toxicity and side effects of synthetic inhibitors have led to a search for new safe and effective tyrosinase inhibitors. Moreover, tyrosinase is also responsible for browning in fruits and vegetables, and thus, inhibitors of this enzyme are frequently applied to plant-based foods.
Search of tyrosinase inhibitors is crucial for the development of skin whitening agents but also anti-browning and insect control substances. A number of researchers have been dedicated to identify inhibitors from natural sources including plants. The largest group of phytochemicals with potent tyrosinase inhibitors belongs to phenolics ranging from the simple ones to polyphenolics [71]. Furthermore, flavonoids occupy the largest portion in newly discovered natural tyrosinase inhibitors, and their structure is compatible with roles of both substrates and inhibitors of tyrosinase [71, 72]. Some flavonoids, such as kaempferol, quercetin, and morin, show inhibitory activity against tyrosinase, while others such as catechin and rhamnetin behave as substrates and suppress tyrosinase activity by being a cofactor (catechin) or acting as a free radical scavenger (rhamnetin) [72]. For instance, steppogenin, a flavanone derivative isolated from
Some stilbenes, such as resveratrol, oxyresveratrol, chlorophorin and andalasin, have also been reported as having tyrosinase inhibitory properties [72, 74, 75]. The most promising inhibitor appears to be oxyresveratrol (32-fold higher inhibitory activity than kojic acid). Some of these compounds are sensitive to photo-oxidation, which limits their use in cosmetic formulations; however, the acetylated resveratrol derivative triacetyl resveratrol is noted to be comparably effective and much more stable than resveratrol [75].
There are also a number of chalcones (the precursors of flavonoids and isoflavonoids), such as licochalcone A, kuraridin, kuraridinol, 2,4,20,40-tetrahydroxy-3-(3-methyl-2-butenyl) and morachalcone A, with remarkable tyrosinase inhibitory activity [72]. Additionally, due to the versatile bioactivity and unique structural motif of chalcones, a number of derivatives have been developed as effective tyrosinase inhibitor candidates.
Although a great number of phenolic compounds revealed tyrosinase inhibitory capacity, the necessity to clarify the viability of these inhibitors in terms of their skin-whitening efficiency has become an urgent task.
The control of some important human diseases includes the use of enzyme inhibitors; however, there is some concern about the use of synthetic inhibitors due to their side effects. Thus, the use of natural enzyme inhibitors, particularly from plant origin, is encouraged nowadays. Indeed, up to date, extensive research has been conducted to study the enzyme inhibitory properties of phenolic compounds. Data revised showed that different phenolic compounds are efficient inhibitors of the activity of a broad number of enzymes linked with important human conditions, such as hypertension, type II diabetes, obesity, Alzheimer’s diseases, inflammation, and skin disorders. It is unmistakable that phenolic compounds are multifunctional compounds that provide a wide spectrum of biological actions beneficial for human health. These compounds exert their action by different mechanisms and have a huge potential in the prevention and treatment of several human diseases. Our bibliographic survey also indicates that flavonoids are probably the group of phenolic compounds with great capacity to inhibit the activity of all the human enzymes analyzed. Several structure-activity relationships studies can be found for some flavonoid compounds. In addition to the enzyme inhibitory capacity, several studies demonstrated the strong antioxidant and anti-inflammatory properties of flavonoids which highlights the relevance of these compounds for the prevention and control of diseases involving oxidative stress or inflammation.
For the future, standardized protocols to search potential inhibitors should be designed in order to minimize the differences among obtained results. Despite the vast number of phenolic compounds studied
This work is supported by National Funds - FCT (Fundação para a Ciência e a Tecnologia, I.P.), through the project UID/BIA/4325/2013. S. Gonçalves acknowledges a grant from the FCT (SFRH/BPD/84112/2012) financed by POPH-QREN and subsidized by the European Science Foundation.
The cerebral venous system (CVS) is a wide, dynamic, and connected net of vessels developing from the encephalic parenchyma to the internal jugular veins (IJVs). As other venous system, it has three main functions: to drain blood and catabolites from the brain, to help maintaining thermic homeostasis and to refill the right-sided heart [1]. Differently from other organs, instead, intracranial veins share unique physiological features and functions. Traditionally, comprehension of CVS has been limited to descriptive anatomy and a few ranges of physiological principles.
New emerging evidences in the last years are depicting a more complex scenario, in which CVS has a pivotal role in starting and sustaining various pathological processes, from multiple sclerosis to cerebral hemorrhages, hydrocephalus, and strokes.
Primitive CVS starts differentiating from primary meninx mesenchyme as a continuous endothelial plexus connecting the dural (
Classically, first clearly identifiable parenchymal vessels are the prootic, the anterior cerebral, and the capitis lateralis and medialis veins [3].
From the 4th to the 5th months, the cortical veins net rapidly grows to sustain the hemisphere fast development. Consequently, the dural sinuses size increases with multiple series of anatomical variations and modifications from week to week. The transverse sinus balloons in response to this increasing amount of blood and to the relatively narrow diameters of jugular vein, with formation and enlargement of multiple emissary vessels for extracranial drainage to the foramen magnum and vertebral plexuses [4]. At the 35-mm stage of the embryo, drainage from the transverse sinus to the IJV can be detected [4].
After birth to the 1st year, the jugular bulb increases in size thanks to the physiological modifications of postnatal circulation, and the drainage through the emissary veins reduces its flow.
Throughout the uterine life, CVS anatomy is dynamically changing in response to the morphometric and hemodynamic adaptations of the growing organism. Progressively, from the chaotic but not homogenous primitive plexus, certain preferential routes are selected on the basis of rheologic flow parameters, while others disappear. The most suitable venous patterns are fixed, independently from our anatomical classifications, similarly to what happens for arteries but with far more variability.
In the ideal description, CVS can be distinguished in parenchymal and dural circulation. It is important to notice that intracranial veins are lacking of intraluminal valves, differently from other veins in the systemic circulation.
The deep parenchymal circulation drains blood from the deep white matter of the cerebral hemisphere, the basal ganglia, and the mesencephalon.
Dural CVS is comprised into the dural sinuses, spaces originated from the splitting of the dura derived from the ectomeninx and covered by endothelium, as above specified.
Arterial blood enters the brain through the anterior circulation, via the carotid arteries, and the posterior circulation, via the vertebral arteries. Also venous blood, or at least the major part of it, exits the brain through an anterior circulation, via the IJVs, and a posterior one, via the vertebral plexuses. Once passed the osteo-dural ring of their respective entry points inside the skull, circulatory physiology of these vessels drastically changes, given the unique physical conditions that are present in the intracranial space.
Although an exhaustive dissertation on cerebrovascular physiology is not in the focus of the present chapter; to understand CVS physiology, few mechanical, hydrostatic, and anatomical principles have to be clarified.
The skull (bone and dura together) is basically a rigid, non-expandable container, totally filled with uncompressible materials: brain parenchyma, blood and cerebrospinal fluid (CSF).
Around 1764, Alexander Monro, second of his name, published
In 1926, Harvey Cushing published “
This is an effective way to summarize the concept, but this formulation lacks the fundamental pulsating nature of cerebral flow. Blood enters the brain pulsating in the arteries; then the mechanical wave of pulsation is transmitted anisotropically through the parenchyma and CSF (fluids with different elastic properties). This wave propagation deeply affects CVS physiology: if blood enters the skull pulsating into the arteries, also it leaves from the vein pulsating.
In this balance of pressure between inflow and outflow, bridging veins have a pivotal role.
A bridging vein is defined as a cortical vessel that drains venous blood from the parenchyma to the sinuses, detaching from the cortex and crossing the subarachnoidal CSF filled and the subdural space. It has thin walls (subdural portion 10–600 μm; subarachnoid space of 50–200 μm) with loose collagen network and no muscular fibers [7]. So constituted, it acts as a perfect Starling resistor: a collapsible tube, filled with a fluid exerting pressure (P1, blood venous pressure), inside a space filled with another fluid exerting a different pressure (P2, CSF/intracranial pressure). To maintain a flow inside the tube, it is necessary that P1 > P2.
While entering, or exiting, the cerebral cortex, the superficial arteries and veins in the subarachnoid space are ensheathed in a leptomeningeal coverage, filled with CSF in a double triangle shape. These invaginations are known as Virchow-Robin spaces in their original description [8] and previously taught to be a virtual space, enlarged only in pathological processes. Further studies during the last decades reassessed the importance of these channels and prosecuted their anatomical micro description, thus renaming it perivascular spaces (PVSs).
Deeper into the parenchyma, PVS surrounds the penetrating arteries and capillaries, and it includes a real space that exists between the endothelial basement membrane (aka
This anatomical description is better defined for the arterial side of cerebral circulation, while venous PVS has not been thoroughly characterized yet.
Intracranial fluids can be divided in intracellular fluid (ICF, 60–70%), interstitial or extracellular fluid (ISF 20% 280–300 mL), blood (10%), and CSF (10% 140–150 mL). Passage of ions, solutes, and molecules between one compartment and the others is precisely regulated to maintain the different chemical composition necessary to their respective physiological role (e.g. plasma contains approximately 270 times more proteins than ISF) [10].
From 2012, a series of experiment on animals and mathematical models led to the discovery and description of the so-called “
The first evidence of an intraparenchymal bulk flow along PVS was provided by Cserr [12] in 1974 by following injected tracers.
Fluid exchanges between venular lumen and paravascular space depend primarily on transmural pressure (TMP), a fundamental hemodynamic parameter. Considering the venous wall as the exchange border for fluids, TMP is a differential pressure between internal (intravenous) pressure (IP) and external (paravascular) pressure (EP). EP is represented by the oncotic pressure of the interstitium plus the intracranial pressure (ICP). IP is the sum of blood pressure and the relative venous oncotic pressure. In turn, each of these parameters depends on several others. Of main interest is that venous pressure of parenchymal vessels depends on bridging veins (Starling resistors) function. To sustain a reabsorption flow from the parenchyma to the CVS, it is necessary that IP is lower than EP.
So, in this paradigm, a dynamic balance between CSF, ICF, ISF, and blood is continuously rearranged throughout the entire vascular, arachnoidal, and ependymal surface to maintain the physiological functions of the estimated 16–30 billion neurons of the brain.
Main driving force of this interstitial convective process is the arterial pulsation of the penetrating arteries, moving actively the CSF along the PVS [9]. Alongside, the periodical variation in ICP is generated by breathing (and similar activities that modify intrathoracic pressure) and vasomotor variations in the vascular net.
Glymphatic system function, defined as the capability of flushes toxic solutes away from the parenchyma, normally decline with aging, both in animals and humans. Proposed mechanism is a reduced CSF interstitial influx secondary to decreased pulsatility of sclerotic arteries, impaired CSF production, and reduced AQP4 expression on astrocytes end feet9. Hypertension and diabetes mellitus type 2 have also been associated with a decreased glymphatic function. Similar observations have been made in cases of stroke, subarachnoid hemorrhage, traumatic brain injury, and demyelination of various origins.
Cerebral vein thrombosis is defined as the presence, in both the cortical vessels and the dural sinuses, of clotted blood impairing physiological flow.
CVT is an uncommon form of stroke (0.5–1% of total), usually affecting young individuals with several associated risk factors (mainly related to Virchow’s triad of blood stasis):
Thrombophilia
Inflammatory bowel disease
Dehydration
Oral contraceptives
Substance abuse
Other more specific associations are made with:
Complication of epidural blood patch
Spontaneous intracranial hypotension
Lumbar puncture
An underestimated risk factor for CVT is a JV thrombosis that propagates cranially, often because of the presence of medical dispositive [13].
Exact epidemiology of CVT is unknown because clinical features are quite variable, and for this reason, cases should be classified differently [16].
Recently, cerebral venous sinus thrombosis in association with COVID-19 has been described, both as a first clinical presentation or a subsequent complication [17].
Clinical findings are related to intracranial hypertension, related to impaired venous drainage, and/or to focal brain injury from venous ischemia or hemorrhage. Obviously, clinical manifestations of CVT also depend on the location of the thrombosis.
Most frequent symptoms are
When CVT is secondary to regional infection, signs and symptom of the primary cause can be detected: toothache and odontogenic abscess; ear discharge; pain in the ear, face, or mastoid region.
In patients with suspected CVT routine, laboratory essay including complete blood count, chemistry panel, prothrombin time, and activated partial thromboplastin time should be performed [9] in order to identify pro-coagulative systemic status. D-dimer assessment makes sense in presence of low pretest probability of CVT to exclude the diagnosis, similarly to pulmonary embolism. Lumbar puncture is characterized by a high opening pressure (80% of cases) but has limited diagnostic value. It is not routinely indicated unless CNS infection is suspected.
Thirty to forty percent of patients with CVT present with an intracranial hemorrhage [18]. Progressively increasing headache over days and alterations in laboratory exams with evidence of hypercoagulability should prompt further radiological assessment for evaluating CVT. Also, at the CT exam, an ischemic/hemorragic lesion that crosses normal arterial boundaries, deep bilateral, or in close proximity to a venous sinus is suggestive of CVT.
Patients complaining of isolated headache and signs or symptoms of intracranial hypertension (papilledema or sixth nerve palsies) should be evaluated for CVT. The correct differential diagnosis between idiopathic intracranial hypertension (IIH) and CVT has therapeutic and prognostic importance. In both cases, however, clinical manifestations are related to the impaired venous outflow function, with subsequent increasing of the ISF.
In a contest of a CVT suspect case, CT without contrast may demonstrate some characteristic features, but an exact diagnosis is made complex by the intrinsic anatomic variability of the venous sinuses and cortical veins. In fact, only in 30% of CVT cases, CT scan shows some abnormalities [19].
The fundamental sign of acute CVT on a CT (without contrast) is a homogenous hyperdensity of a cortical vein or sinus. Another typical sign of the superior sagittal sinus thrombosis (posterior portion) is the filled delta sign, a dense triangle in the context of the sinus.
Only 0.5–0.8% of patients with CVT showed some signs of subarachnoid hemorrhage, often in atypical position.
The contrast-enhancing CT scan could add some clues, such as the classic “empty delta” sign: an enhancement of the dural border of the sinus with a filling defect within it due to the thrombus in a triangular shape.
This is not a precocious finding, but usually lasts for several weeks after the acute phase.
On the other hand, CT venography is much more useful in chronic follow-up because the occluded sinus cavity shows a variable density. The presence of cortical bone close to the dural sinus can produce interfering artifacts during the visualization of the enhanced dural sinus.
Classically inside the normal sinus, there is a flow void signal due to the venous stream continuously moving. Early signs of CVT can be visualized as
Meanwhile, an acute thrombus, not fully formed yet, may appear as a hypointense signal, similar to the normal flow void.
Other signs include cerebral swelling, edema, and/or hemorrhage. Diffusion-weighted imaging (DWI) sequences show hyperintense signal, meaning a reduced blood flow, with a prognostic significance: brightening sinus on DWI predict low chances of recanalization.
Magnetic resonance imaging (MRI) is particularly helpful in defining the nature and extension of parenchymal lesions, causes, or consequences of the CVT: focal edema, infarction, and infectious processes.
MRI venography is the most common CVT diagnostic technique with the use of two-dimensional time-of-flight (TOF) sequences because of its excellent sensitivity to slow flow inside the sinus.
Venous phase of cerebral angiography (4–8 s from the injections) typically, and directly, shows a filling defect in the occluded lumen. Other signs are venous congestion with dilated cortical, scalp, or facial veins, enlargement of collateral drainage, and venous flow reversal.
Although it is an invasive procedure, cerebral angiography (or venography) could help to solve undefined situations due to anatomic variations such as sinus atresia/hypoplasia, asymmetrical drainage, and normal sinus filling defects caused by arachnoid granulations or septa.
Most used therapeutic approach is based on blood anticoagulation, which aims to prevent thrombus growth, avoids development of pulmonary embolism, and promotes sinus recanalization. Different drugs and different strategies are present in literature [16], with the use of unfractionated heparin (UFH), antivitamin K molecules, low-molecular-weight heparin (LMWH), and low-dose unfractionated heparin. An effective treatment is complicated by the presence of intracranial hemorrhage or cerebral infarction at the time of the diagnosis, given the increased risk of worsening the bleeding.
The available data from RCT comparing clinical/radiological outcomes and bleeding complications support a safe and effective role for anticoagulation in the treatment of CVT, even if intracranial bleeding is present [16]. There are no data that suggest the preferential use of UFH or LMWH in CVT patients. Some data suggest that, if pulmonary embolism or deep vein thrombosis is present, LMWH have to be preferred [20].
In case of secondary CVT (infection, trauma, and other transient causes) vitamin-k antagonist should be continued for 6 months after the removal of the causative factor [16].
Otherwise, in case of primary CVT, vitamin-k antagonist should be continued for 6–12 months and further coagulative assessment should be carried on [16].
Other therapeutic options include
Cerebrospinal venous insufficiency is an emerging nosological entity collecting different conditions that shares an impaired venous outflow from the brain to the heart. Multiple central nervous system disorders, such as idiopathic intracranial hypertension (IIH), Ménière disease, transient monocular blindness, and Alzheimer’s disease, have already been reported to be associated with internal jugular vein (IJV) stenosis [22, 23]. Nowadays, different branches of medical sciences are directing their attention to the delicate balance between cerebral inflow and outflow in order to better understand CVS physiology and its correlation with several disorders. As a mechanical system, a CVS flow obstruction from any causes at any level lead to an increased pressure transmitted upward. This means an increased capillary pressure, thus an increased TMP and finally a decreased glymphatic paravascular ISF flushing and reabsorption into the CVS. Proceeding from the parenchyma to the major vessels, venous convergence reduces the possibility of alternatively restoring a fully functioning flow. Once in the IJV, collateral drainages are few and of limited caliber. So, at this level, any stenosis (intraluminal, parietal, or extraluminal) produce effects diffused at the entire CVS and to the parenchyma. In the mathematical Gadda-Ursino hemodynamic model of CVS outflow, a jugular stenosis is a significant parameter in sinus pressure regulation [24].
Over the last years, several new pathologies have been described related to IJV obstruction, and old ones received new interpretations.
Usually, patients suffering from IIH are women with elevated BMI and normal to slit cerebral ventricles [25]. Meanwhile, IIH has a strong relation with impaired CVS outflow caused by increased thoracic-abdominal or dural sinuses pressure (obesity, CVT, and superior vena cava syndrome). On the other hand, acutely dilated ventricles are related to high-pressure hydrocephalus caused by cerebrovascular pathology (infection, trauma, and hemorrhage).
Recently, an anomalous IIH case with dilated ventricle (Evans index 0.36) has been described in a woman with normal BMI complaining of headache, visual loss (Frisen grade 4 papilledema), and pulsating tinnitus. Neuroimaging did not reveal any causes of hydrocephalus from intracranial lesions, while a fluorodeoxyglucose (FDG) positron emission tomography (PET) described a diffuse hypometabolic cerebral state.
At B-mode echography of extracranial IJV, a bilateral external compression from omohyoid muscle was demonstrated, hemodynamically corresponding to blocked venous flow with scarce collateral compensation.
The patient underwent surgical bilateral resection of omohyoid muscle with ICP invasive monitoring. After transection of the muscles, a sudden drop in ICP and normalization of ICP wave were observed.
Headache and tinnitus disappeared after surgery, and papilledema progressively improved with visual acuity restoration. Serial (24 months’ follow-up) MRI documented regression of Evans index and FDG-PET showed improvement of brain metabolism.
These peculiar cases led to the description of a new clinical entity, a form of hydrocephalus that does not require CSF shunt procedures. This syndrome has been called JEDI (jugular entrapment dilated ventricles intracranial hypertension) syndrome [26]. While an extracranial obstacle to CVS is coherent with intracranial hypertension for the aforementioned principles, it is still unclear what caused ventricles dilatation in this case. More studies are needed to fully comprehend the relation between IJV obstruction, IIH, and hydrocephalus.
In 1937, the American otolaryngologist Dr. Eagle was the first to describe a clinical syndrome caused by an elongated styloid process [27]. The stylohyoid complex is composed of styloid process, stylohyoid ligament, and the lesser horn of the hyoid bone. The styloid bone starts from the inferior portion of the temporal bone, just medially to the base of mastoid process, and directs inferiorly, medially, and anteriorly, passing anteriorly and laterally to the C1 anterior arch and transverse process. These anatomical structures embriologically originate from Reichert’s cartilage of the second brachial arch.
Classic Eagle syndrome is mainly characterized by pain, dysphagia and otalgia, often exacerbated by yawning and swallowing, arising after a tonsillectomy. It is thought that postsurgical scar tissue stretches the sensory nerves ending in the peri-pharingeal region [28].
The carotid artery variant of Eagle syndrome is due to the impingement between an elongated styloid process and the carotid artery and associated nerves. It is characterized by pain and an increased risk of cerebrovascular ischemic accidents: arterial dissection, obstruction, transient ischemic attack, and stroke.
A third variant of the syndrome has been described, consisting in an IJV compressed by an elongated styloid process in the passage adjacent to the transverse process of C1. The most common involved jugular segment is J3, and in more than 50% of patients the stenosis is bilateral. It is alternatively named “
This latter form of Eagle syndrome has specific features related to an impaired CVS outflow.
Clinical presentation is frequently nonspecific. Most frequent symptoms are
More peculiar, an
It is more common in young adults (mean age of onset 38.6 years) with no prevalence between sex.
In literature, only 1/3 of patients with diagnosed Eagle jugular syndrome have an effectively elongated styloid process. This suggests that even with a normal length, an abnormally narrow space between the styloid process and C1 transverse process may lead to IJV compression [30].
Diagnosis is classically radiological, with direct evidence of impaired IJV flow (MRI venography or angiographic venography) or indirect proof of a narrowed C1-styloid space (CT scan or MRI). Few criteria have been proposed, and not diffusely shared between studies, to define a significant IJV stenosis in a setting of suspected Eagle jugular syndrome. According to Jayaraman [31], a jugular stenosis is defined as a caliber reduction >80% on axial cuts compared with the normal vein proximal to the stenosis. Ding and Bai [32] proposed other similar criteria.
More frequently, a conservative treatment is preferred with anticoagulant usage, but in most cases medical therapy has shown no effectiveness on symptoms control.
Invasive procedures are surgical (styloidectomy, C1 anterior arch removal), endovascular (ballooning or stenting), or combination of both. Styloidectomy is the most frequently performed surgical procedure, and major risks are vascular or facial nerve injuries.
On the other side, endovascular treatments are associated with stent migration or fracture, pseudoaneurysm formation, thrombosis, and cranial nerve injuries.
After an invasive approach, more than 70% of patients report an improvement in tinnitus, papilledema, and visual disturbances. Headache, the most frequent symptom, and dizziness usually do not respond to the treatment.
One of the major issues still open regarding the Eagle jugular syndrome is the lack of standardized data, especially on IJV pressure, flow velocity, and collateral pathways. Thus, a complete understanding of pathogenesis is missing.
Multiple sclerosis is a complex autoimmune demyelinating disease characterized by a chronic inflammatory response against the CNS. Many aspects of this disease are still unknown, but evidences have increased, through the last decades, pointing toward a fundamental involvement of CVS in the early development of it.
A cardinal observation is that each MS lesion is crossed and split by a central vein, that is to say that demyelination and inflammatory infiltration develop around a vein [33].
From a wider point of view, inflammatory processes in MS seem to be concentrated around venular vessels, more than capillary or arterial [34].
From these data, and others, an association has been proposed between MS and chronic cerebrospinal venous insufficiency (CCSVI), a condition of long-lasting impaired venous drainage from CVS caused by obstruction in extracranial veins. Recently, CCSVI has been associated also with other degenerative processes such as Alzheimer’s disease, Parkinson’s disease, and Meniere’s disease.
A defective valve, hypoplasia, and/or compression of the IJV or the azygos vein, as defined earlier, increase TMP and reduce the ability of glymphatic system to drain toxic catabolites from the interstitium. These peptides then accumulate at the perivenular level and may act as first inflammatory chemotactic activators and further increase oncotic pressure into the perivascular space, worsening the ISF resorption capacity. Generally, perivenular spaces are recognized as an important site of leukocyte trafficking and the potential milestones to modulate immune response.
Measuring CSF dynamic with MRI reveals interesting links between venous function and MS. In clinically isolated syndrome (CIS), conversion to clinically definite MS in the following year has been related to CSF net flow decreasing [35]. In relapsing-remitting MS, a significant reduction in CSF flow at the level of the Sylvius aqueduct was observed compared to control groups [36]. In the early and progressive form of MS, an increase in ventricular dimension has been observed during the first year. This may be related to the impaired function of glymphatic system, and there are evidences that in these patients, a therapeutic flow restoration through endovascular recanalization of IJV is linked to a significant reduction in ventricles and subarachnoid spaces dimension [37].
Moreover, CCSVI is an ultimate cause of decreased cerebral perfusion because of the propagation of retrograde hypertension. There is a linear correlation between flow into the IJV and global brain perfusion [38]. Moreover, in MS, hypoperfusion is a pathological key point that precedes plaque formation and could be a causative agent, provoking damages to the oxygen-dependent oligodendrocytes. Myelin loss and debris occur when the metabolism of these cells is altered, and this is an important inflammatory signal that attracts leukocytes. Thus, inflammation seems to be a consequence, more than a cause [39]. Subsequent BBB disruption causes microbleedings, and iron deposition, coming from hemoglobin degradation, further increases inflammatory response and microbleedings, especially around venular vessels. Consistently, cerebral tissue iron loading correlates with MS-related disability at the Expanded Disability Status Scale (EDSS) [40].
A subarachnoidal hemorrhage (SAH) not caused by vascular malformation (such as aneurysm or arteriovenous malformation (AVM) rupture) is a recognized clinical entity usually referred as
It typically presents with a pattern limited to the perimesencephalic cisterns (typical pattern), sometimes extended to the nearer basal cisterns (atypical pattern). In the majority of cases, the clinical course is benign, with a very low rate of recurrence. At the neuroimaging, no causes of bleeding are detected, neither immediately or later. Pathogenesis of na-SAH is not established, but the most shared hypothesis regards anatomic variations of CVS, particularly of the Basal Vein of Rosenthal (BVR) draining into venous systems different from the Galenic one. CVS hypertension has also been occasionally reported to influence the overall risk of na-SAH in various conditions, such as cavernous sinus thrombosis, transverse sinus thrombosis, or a bilateral jugular venous obstruction.
In a retrospective case-control study, a significant association has been made between na-SAH and the presence of an IJV stenosis (>80% of caliber reduction) at the passage through the styloid process and the arch of C1 [41]. Also, older age and diabetes were statistically linked to an increased risk of na-SAH.
This is coherent with what has been reported before: an impaired CVS outflow due to a stenosis leads to increased venular pressure, thus predisposing wall rupture and bleeding when an adjunctive pressure is applied (e.g. physical exertion). The presence of anatomic variations may be a further element that increases the risk of na-SAH, but, in the end, the way in which venous configuration of the perimesencephalic area might predispose to bleeding remains undetermined.
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