Studies investigating the relevance of endocannabinoid system in HD pathogenesis in animal models. Studies are presented in chronological order.
\r\n\tHomeostasis is brought about by a natural resistance to change when already in the optimal conditions, and equilibrium is maintained by many regulatory mechanisms. All homeostatic control mechanisms have at least three interdependent components for the variable to be regulated: a receptor, a control center, and an effector. The receptor is the sensing component that monitors and responds to changes in the environment, either external or internal. Receptors include thermoreceptors and mechanoreceptors. Control centers include the respiratory center and the renin-angiotensin system. An effector is a target acted on to bring about the change back to the normal state. At the cellular level, receptors include nuclear receptors that bring about changes in gene expression through up-regulation or down-regulation and act in negative feedback mechanisms. An example of this is in the control of bile acids in the liver.
\r\n\tSome centers, such as the renin-angiotensin system, control more than one variable. When the receptor senses a stimulus, it reacts by sending action potentials to a control center. The control center sets the maintenance range—the acceptable upper and lower limits—for the particular variable, such as temperature. The control center responds to the signal by determining an appropriate response and sending signals to an effector, which can be one or more muscles, an organ, or a gland. When the signal is received and acted on, negative feedback is provided to the receptor that stops the need for further signaling.
\r\n\tThe cannabinoid receptor type 1 (CB1), located at the presynaptic neuron, is a receptor that can stop stressful neurotransmitter release to the postsynaptic neuron; it is activated by endocannabinoids (ECs) such as anandamide (N-arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG) via a retrograde signaling process in which these compounds are synthesized by and released from postsynaptic neurons, and travel back to the presynaptic terminal to bind to the CB1 receptor for modulation of neurotransmitter release to obtain homeostasis.
\r\n\tThe polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) and are synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs) mediate significant effects in the fine-tuning adjustment of body homeostasis.
\r\n\t
\r\n\tThe aim of this book is to discuss further various aspects of homeostasis, information that we hope to be useful to scientists, clinicians, and the wider public alike.
The human body is prone to many virulent microbes and their oxidative metabolic substances. The human body is shielded from potentially pathogenic microbes by the immune system [1]. The gastrointestinal tract, which is approximately 7.5 meters long, is the largest area of the immune system. Furthermore, trillions of bacteria reside in the gut, particularly in the colon, which served as the main reservoir for these mutualistic species. Most of the time, it is said that the number of human cells in the body is ten times less than that of bacterial cells, while this proportion has been revamped to about 1:1 [2]. Normal vaginal and fecal microorganisms were injected at birth to study the host microbe’s relationship with the newborn. This inoculum contains aerobic, anaerobic, gram-positive, and gram-negative bacteria belonging to dominant species such as Sneathia spp., Lactobacillus spp., and Prevotella spp. [3]. It has been studied that how gestational stage, environment, type of delivery, attitude, and breastfeeding habits influenced the proliferation and stability of the infant’s microbiome [4].
The host-microbe relationship is critical for the growth of the gastrointestinal immunity within the first weeks after giving birth. The proliferation and growth of gut microorganisms continues until about the age of two years, at which point the intestinal immune system is said to be mature [5]. The intestinal environment of gut microorganisms is generally stable, particularly at the species and genus levels. Besides that, irrational antibiotic use, pathogenic parasites, malnutrition, or cold and hot stress all have an impact on the structural composition of gut microbiota [6].
Antimicrobial drugs, as well as human-targeted medicines, have been attributed to changes in gut microbial composition. More than a thousand antimicrobial drugs have been evaluated against forty different intestinal bacteria around the world. They discover 24 drugs that inhibit the growth of one or even more bacterial strains in vitro [7]. The defensive mechanism is triggered by innate immunity when an individual’s body is exposed to a foreign particle or sustains tissue damage. Innate immunity protects cells physiology by signaling adaptive immune responses to persistent threats and stimulating inflammatory response. Inconsistent innate and adaptive responses, on the other hand, result in highly inflammatory reactions, tissue damage, and disease. The host mucosal immune response induced by gut microbiota is important for maintaining intestinal homeostasis and developing a systemic defense response. Manipulation of the intestinal microbiota can thus be a viable alternative route to improving health and to prevent and/or cure illness [8].
Probiotics were described as ‘live microorganisms that impart benefits to the host health when taken in sufficient quantities as component of food”. Saccharomyces, Lactobacillus, and Bifidobacterium are three important probiotic Genus that have been extensively researched and used in animal and human feed [9]. Recent research indicates that probiotics have a number of beneficial effects on the host’s gastrointestinal tract protection mechanism. They produce bactericidal substances by which they counteract pathogenic microorganisms’ consequences and bind to the intestinal epithelium by interacting with pathogenic microorganisms and their toxins. Probiotics facilitate the longevity of epithelial cells, improve the immune barrier, and improve the immune response to intestinal epithelium, all of which lead to gastric mucosal homeostasis [10]. Most notably, immune system regulation is among the most potential factors behind probiotics’ beneficial health effects. Probiotics strengthen innate and adaptive immunity and suppress bacterial infection through toll-like receptor-regulated signal transduction pathways. Probiotic bacteria have been seen to enhance intrinsic host immune mechanisms. The use of probiotic microbes has significant effects on people’s immune systems, such as stabilizing the non-immunological or innate immune response triggered by gut microbes, improving adaptive intestinal immune response, and regulating non-specific inflammatory and hypersensitivity reactions [11].
The concept of probiotics therapy emerged after the discovery of gut microbiome that is an inherent part of the intestinal epithelial cells. A probiotic is represented as a live microorganism’s dietary supplement that benefits the individual by boosting the intestinal microbiome in the gastrointestinal tract. The probiotic definition is incomplete for the aim of human health and nutrition. In response, the European Commission and the International Institute of Life Sciences collaborated to reframe the concept of probiotics as a live microbial food item which is beneficial to human health [12].
In 1953, German researcher Werner Kollath coined the term probiotic, which is comes from the Latin terms pro, which means for, and biotic, which means “bios” or “life.” Probiotics were defined by Lilly and Stillwell in 1965 as substances produced naturally by one microorganism that promotes the growth of another. In 1992, Fuller described probiotics as “live microorganisms added as a supplement in feed that benefits the host by improving its intestinal microbial balance” Probiotics have a modern history dating back to the early 1900s, when future Nobel laureate Elie Metchnikoff, a Russian scientist working at the Pasteur Institute in Paris, performed groundbreaking research [13].
Louis Pasteur established the microbes required for the fermentation process, while Metchnikoff first sought to determine the potential impact of the microbiota on public health. He attributed Bulgarian village peoples’ long life spans to their regular consumption of yoghurt, which are fermented dairy products. He related this to Stamen Grigorov, a physician who found the Bulgarian bacillus, and further proposed that lactobacilli could mitigate the decaying impact of digestive fermentation, that led to illness and aging. Furthermore, Socrates said over two thousand years ago that “death lies in the guts” and that “poor absorption is the root of all evil.” Metchnikoff also reported that toxins generated by microbial decomposition in the gastrointestinal tract and then discharged into to the bloodstream trigger aging [14]. Such microbes were originally referred to as decomposing microbes, but they are now known as proteolytic clostridia. Metchnikoff also noted that “the gastrointestinal microbiota’ reliance on food allows us to take steps to change the microbiome in our gastrointestinal tract and exchange pathogenic microorganisms with good bacteria.” Metchnikoff scientific theory of probiotics was the foundation for the first dairy industry in France [15].
Modern techniques have selected probiotics strains that manufacture fortified milk with strong nutritional and organoleptic features more than anyone else. Yoghurt was the first functional fermented food based to historical evidence [16]. However, since probiotics are usually associated to the consumption of fermented foods, they have a long and distinguished history. In ancient Indian Vedic literature, milk and milk products are associated to a reliable and comfortable life. According to legend, the first kefir grain was distributed by Prophet Muhammad (SAW) to the descendants of Caucasian mountaineers as a reward. Kefir is a fermented milk drink that contains a lot of lactic acid bacteria and probiotics. Cheese and yoghurt have been used by Hippocrates, Marco Polo, Galeno, and Chinese people throughout history [17].
The most distinguished cells of natural immunity in probiotic research are the dendritic and epithelial cells. These are the first cells to interact with the gut microbiota and its toxic metabolites. Gut associated lymphoid tissue (GALT) and intestinal mucosa is the reservoir of intestinal dendritic cells. Dendritic cells are also known as detector cells because they have unique receptors that attach to specific sites on pathogen surfaces. Dendritic cells also act as a catalyst for various forms of signaling pathways that modify phenotypes and secreted cytokines such as Toll-like receptors and c-type lectin receptors [18].
The use of probiotic strain
The absorptive role of intestinal epithelium is well described. Epithelial cells produce a mucosal barrier to safeguard the individual from harmful microbes and toxicants. The intestinal mucosa barrier has a powerful connection with the intrinsic immune system of the Peyer’s patches and lamina propria [24]. Probiotics are well-known for preserving the integrity of the intestinal barrier through a variety of mechanisms, including starvation of infectious agents as they compete for nutrients, detachment of bacteria from intestinal epithelium, which prevents pathogen invasion, immune response regulation, and aiding in regulatory T cell responses. Most of these are probiotics’ positive effects on the host’s internal health [25]. The use of
Multiple probiotic strains of the genus Bifidobacterium, such as
Probiotics are used to sensitize the host’s immune system to potentially dangerous pathogens. Oral administration of B. bifidum increased humoral immune response to egg albumin, whereas
Probiotic derived proteases have been shown to digest cow milk casein and produce peptides that inhibit inflammatory cytokines in healthy people. A study was conducted to see whether caseins digested by probiotic bacteria producing proteases might induce the production of cytokine and anti-CD3 immunoglobulin mononuclear cells in atopic dermatitis in infants with cow milk allergies. Casein from cow’s milk stimulates the synthesis of IL-4, which causes hypersensitivity [35]. Oral administration of
The ability of probiotics to increase the number of T-regulated lymphocytic cells contributes for their anti-inflammatory and anti-colitis properties.
Probiotics strain produced short chain fatty acids molecules such as propionate, isobutyrate, acetate, butyrate etc., which directly or indirectly regulate the homeostasis of T-cells. Butyrate activates Foxp3+ cells and Treg cell production outside of the hypothalamus. Propionate regulated the production of T-cell by inhibiting histone deacetylase. Probiotics e.g.
Probiotics have the ability to shift the immune response from Th2 to Th1. L. casei can stimulate IL-12 development, polarizing the Th1 response and mitigating Th2 linked illnesses.
Probiotics have a direct effect on the cells of the lamina propria and payers patches, resulting in an increase in IgA production cells. IgA plays an important function in the prevention of mucosal pathogens. Toxins are neutralized by IgA, which prevents pathogens bacteria from binding to intestinal epithelial cells.
The oral cavity is a highly complex structure containing over 700 different types of bacteria. When there is a disturbance in this environment, abnormalities such as periodontal disease may occur, resulting in a reduction of indigenous microbial populations to the advantage of infectious agents. The causative agents of oral cavity disease are
Anti-bacterial substances formed by probiotic strains included defensin, acetaldehydes, hydrogen peroxide, bacteriocins, organic acids, ethanol, and peptides. Peptides and bacteriocins, in general, are essential in increasing the vascular permeability of target cells that contributes to activation of the membrane permeability and, eventually, cell damage [44].
Probiotics have antibacterial effect, which is an essential feature. Bacteriocin synthesis may be one way to accomplish this antibacterial activity. Bacteriocins are produced by the industrial probiotic strains
The most commonly used probiotic strains are from the Lactobacillus genus, which is recognized as safe. Some researchers have explained the function of probiotics in the buccal mucosa during the last few decades. Intake of lactic acid bacteria containing items has been shown to mitigate dental caries of mutant streptococci, but the studied species were ATCC strains rather than standard probiotic species such as
A number of microorganisms have been found in the human respiratory tract as the primary source of the respiratory virus. We may reduce the occurrence of disease development in humans by limiting the penetration of respiratory tract viruses into the membranes of mucosal epithelial cells. The human body contains a diverse community of mutually advantageous commensal bacteria known as microbiota [49]. Probiotics are microorganisms that have potential health benefits when eaten in a specific amount. There are two basic types of probiotics: Lactobacillus and Bifidobacterium and Both have a positive impact on human health since it acts as an antiviral agent, lowering the binding ability of viruses to the host receptor and thereby capturing the virus. Probiotics administering protects individuals from various respiratory viral infections like Respiratory syncytial virus, SARS-CoV-2, Influenza A virus. This antiviral activity was investigated by the strain’s specificity as well as the host immune status [50].
The COVID-19 disease affects the lungs and the gastrointestinal tract, inducing pro-inflammatory Th1-cells to release various cytokines such as TNF-alpha leading to the establishment of the cytokine storm. Dysregulation in the intestinal microbiome contributes to an imbalance of Th1 and Th2, which stimulates the formation of pro-inflammatory cytokines and, eventually, a cytokine storm in epithelial cells in the lungs [57]. Probiotics promote the proliferation of “beneficial bacteria” in the intestine, resulting in a change in the stability of Th1/Th2 cells, which lowers the cytokine storm and the severity of infections. It was recently found that using probiotic bacteria derived from Lactobacillus and Bifidobacterium improves the chance of healing from COVID-19 patients.
The global fungal load is extremely high, and it is expected to rise even higher as the proportion of immunocompromised people rises. In contrast, the drugs used to treat fungal pollutions are extremely small, and some of them are extremely dangerous.
Aflatoxin is an extremely hepatotoxic bioactive compound produced by fungi, which is a major global concern. A toxin-free feed is demanded by the existing agriculture and livestock production industries. Use of such microbes to food preservation has grown in popularity in recent years, owing to customer needs for less reliance on chemical preservatives. Lactic acid bacteria are widely regarded as a “beneficial organism,” that is used to avoid contamination of food and feed, as well as to chemically store food. It is also intended to produce antimicrobial agents [60].
Probiotics have been shown to decrease
Nowadays, the discovery of the use of probiotic strains has improved our understanding of the relationship between diet and people’s health. Probiotics boost innate and humoral immunity against pathogens. Probiotic bacteria bind to gut epithelial cells and release cytokines (IFN-γ) and interleukins (IL-10) that establish a microclimate in the tracheae, bronchi, and reproductive organs and gut lamina propria, triggering clonal proliferation of B cells to make IgA and activating Treg cells, thereby maintaining immune balance in the gastrointestinal tract. COVID-19 is a newly emerging virus that causes deadly disease all over the world. Probiotic strains, especially lactobacillus species therapy, may be critical in controlling COVID-19, and probiotic treatment may be considered as a choice for the reduction and mitigation of COVID-19 infection globally.
The authors declare no conflict of interest.
Huntington’s disease (HD) is a neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline as well as psychiatric disturbance [1, 2]. The prevalence of HD is estimated to be between 0.4 and 5.70 per 100,000. Since HD is a genetic disorder, the prevalence depends strongly on the study population and it is higher in Europe, North America, and Australia than in Asia [3]. HD is caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). The disease develops in individuals bearing a number of repetitions greater than 40, whereby greater CAG repeats found in the huntingtin gene are associated with early-onset forms of the disorder, fast rate of disease progression, and the most severe neurological deficits [4].
The mean age of HD onset is around 40 years, meanwhile the Juvenile Onset Huntington’s Disease (JOHD), occurs in individuals bearing more than 60 CAG repeats, which usually starts at the age of 21. HD eventually leads to death 15–20 years after the symptomatic onset [5]. It is believed that mutant huntingtin (mHTT) affects many cellular functions and leads to cell death, preferentially subpopulations of GABAergic medium spiny projection neurons and neurons in the cerebral cortex [1, 6]. This leads to imbalances in diverse neurotransmission, including the dopaminergic (DA) and glutaminergic systems. In the early stages of HD, DA neurotransmission is increased, whereas expression of DA receptors is reduced. However, in the course of the disease DA neurotransmission decreases. In turn, time-dependent abnormal DA neurotransmission affects glutamate receptor modulation, which may cause excitotoxicity [7, 8]. As DA plays a crucial role in the control of coordinated movements, motivation, and reward as well as cognitive function, alterations in DA balance in the striatum and provoke neurological and psychiatric symptoms of HD. The early stages of the disease are often characterized by chorea, followed by akinesia, while dystonia is more typical for the late stages [9]. Major non-motor symptoms include apathy and depression, anxiety, irritability, or aggressive behavior [9]. Impairment in cognitive functioning eventually ending in dementia, which has been mentioned by George Huntington in his first report, is another integral part of the disease [10]. Until today, there is no cure for HD, and treatment is only symptomatic, targeting mainly dopaminergic and glutaminergic systems [11].
Over the last 30 years, the endocannabinoid system (ECS) has emerged as an important neuromodulatory system, which could be efficiently targeted in a number of neurological diseases, including HD [8, 12, 13]. The primary cannabinoid receptor subtypes are cannabinoid receptors type 1 (CB1) and type 2 (CB2). The CB1 receptor is a protein-coupled receptor, highly expressed in the central nervous system (CNS), particularly in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem. In addition to its CNS location, CB1 has also been identified in numerous peripheral tissues and cell types [14]. On the other hand, the CB2 receptor is expressed mainly outside CNS, predominantly in the immune system. However, it has also been identified in the CNS, especially in the glial cells and brainstem neurons [15, 16]. The abovementioned high distribution of the CB1 receptor in basal ganglia indicates an indispensable role of the ECS in the control of movements by inhibitory modulation of other neurotransmitter systems [16]. Moreover, the CB1 receptors regulate glutamatergic neurotransmission under both physiological and pathological conditions and thus are able to downregulate excitotoxic glutamate release [17].
Studies in animal models suggest that the pathogenesis of HD may be related to an early and widespread reduction in the ECS, particularly to the loss of CB1 receptors [16, 18, 19] and decreased endocannabinoid levels in the striatum, which in turn may lead to hyperkinesia [19]. The administration of substances, which increase endocannabinoid activity led to a significant improvement of motor disturbances in a rat model of HD [16, 20]. In particular, Lastres-Becker et al. [17] hypothesized that substances that increase the endocannabinoid activity could be applied for the treatment of hyperkinetic symptoms. To test this hypothesis the authors created a rat model of HD through bilateral striatal injections of 3-nitropionic acid that leads to impaired striatal GABAergic neurotransmission. As a result, these rats started suffering from abnormal movements followed by motor depression. In addition, they demonstrated that the severity of motor hyperkinesias was correlated with decreased concentration of several neurotransmitters, such as GABA, dopamine, and their metabolites. Moreover, mRNA levels for the CB1 receptor were depleted in the caudate-putamen of 3-nitropropionic acid (3-NP) injected rats. In addition, the authors demonstrated a reduction in CB1 receptor binding in the caudate-putamen, the globus pallidus, and also substantia nigra. Finally, the administration of AM404, an inhibitor of endocannabinoid uptake, led to the alleviation of motor disturbances. The same group from Madrid [21] explored the status of CB1 receptors in the HD94 transgenic mouse model of HD. To investigate this problem, the authors analyzed mRNA levels of the CB1 receptor and the number of specific binding sites, and the activation of GTP-binding proteins by the CB1 receptor agonist. As a result, they have demonstrated that mRNA transcripts of the CB1 receptor were significantly decreased in selected regions of the brain, such as caudate in the HD transgenic mice compared to controls. This depletion was correlated with a marked reduction of reception density in the caudate, globus pallidus, and substantia nigra pars reticulata. In addition, the efficacy of CB1 receptor activation was depleted in the globus pallidus and there was a trend toward a decrease in substantia nigra.
Another significant contribution was done by the group from the Autonomous University in Madrid led by Isabel Lastres-Becker [22]. The scientists used a previously mentioned rat model of HD for this purpose created via bilateral intrastriatal injections of 3-NP. As a result, CB1 receptor binding and activation of GTP-binding proteins were also reduced in the basal ganglia. In parallel, the authors demonstrated a significant decrease of two endocannabinoids, anandamide and 2-arachidonoylglycerol in the striatum of affected rats, while there was an increase in anandamide concentration in the substantia nigra. Importantly, both CB1 receptors concentration, as well as endocannabinoid levels, were not changed in the cerebral cortex. Another study by the same group [23] has shown that compounds acting at the endocannabinoid systems reduce hyperkinesia in a rat model of HD. In particular, they applied AM404, an inhibitor of the endocannabinoid reuptake, which was able to reduce hyperkinesia and provoke recovery from neurochemical deficits.
As for exocannabinoids used in the treatment of neurological and psychiatric disorders, in one study [24], delta9-tetrahydrocannabinol (THC), a nonselective cannabinoid receptor agonist, and SR141716, a selective antagonist for the CB1 receptor, were tested in an animal model of HD. Surprisingly enough, the administration of THC increased malonate-induced striatal lesions, but SR141716 enhanced the same effect to an even greater extent. Another study examined the long-term effects of exocannabinoid exposure in animal models of HD. In this case, they used transgenic mice R6/1 of HD and administered THC for 8 weeks. This chronic treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration.
Similarly, Sagredo et al. [25] examined the neuroprotective effect of cannabinoids in rats with 3NP striatal lesions. To tackle this question, the authors used the CB1 agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 agonist HU-308, and cannabidiol (CBD). Interestingly enough, the application of CBD, but not ACEA or HU-308 reversed the effects of 3NP. In particular, CBD reversed 3NP-induced reductions in GABA contents and mRNA levels of substance P (SP), neuronal-specific enolase (NSE), and superoxide dismutase-2 (SOD-2). The authors concluded that CBD has neuroprotective values, but mainly on striatal neurons projecting to substantia nigra. This neuroprotective effect was not reversed by the CB1 receptor antagonist SR141716. Pintor et al. [26] demonstrated that the cannabinoid receptor agonist, WIN 55,212–2, attenuates the effects induced by quinolinic acid (QA) in the rat striatum. In this study, QA was introduced in the rat striatum and this, in turn, led to the reproduction of clinical features typical for HD. The administration of WIN 55,212–2 blocked the increase in extracellular glutamate induced by QA. During
Another study by de Lago et al. [29] examined whether arvanil, an endocannabinoid „hybrid,” could lead to symptom reduction in the rat model of HD. It was demonstrated that arvanil reduced ambulation and stereotypic movements. The same group [30] demonstrated that UCM707, an inhibitor of the anandamide uptake, could be used as a symptom control agent in an animal model of HD and multiple sclerosis (MS), but failed to delay the disease progression.
Furthermore, a number of other studies have suggested that therapies with CB-activating compounds might lead to neuroprotective effects against excitotoxic striatal toxicity through both CB receptor-mediated and independent effects [21, 31, 32, 33, 34, 35]. However, in several studies, no benefit or even exacerbation of neurotoxicity could be observed [22, 25, 29].
An overview of studies investigating the relevance of the endocannabinoid system in HD pathogenesis in animal models is shown in Table 1.
Reference | Model | Substance | Outcome |
---|---|---|---|
Lastres-Becker et al. [17] | 3 NP rats |
| AM404 reduced motor hyperactivity and improved toxin-induced GABA and dopamine deficits. |
Lastres-Becker et al. [23] | 3 NP rats |
| AM404 reduced hyperkinesia in lesioned animals VDM11 and AM374 did not improve hyperkinesia. Capsaicin and CP55,940 reduced hyperkinesia. Capsaicin improved GABA and dopamine deficits in basal ganglia. |
Lastres-Becker et al. [24] | Malonate rats |
| Exacerbation of neurotoxicity. |
Lastres-Becker et al. [36] | 3NP rats |
| Neuroprotection. |
De Lago et al. [21] | 3 NP rats |
| Arvanil showed anti-hyperkinetic effects and increased the content of glutamate in the globus pallidus. |
Pintor et al. [26] | Quinolinic acid rats |
| WIN55,212-2 showed neuroprotective effects and AM-251 reversed them. |
De Lago et al. [30] | Malonate rats |
| Reduction of hyperkinetic activity and increase both glutamate and GABA levels in the globus pallidus. No neuroprotection. |
Sagredo et al. [25] | 3 NP rats |
| Neuroprotection. |
Sagredo et al. [28] | 1. Malonate mice 2. CB2R knockout mice |
| HU-308 was neuroprotective and reduced proinflammatory markers (TNF-alpha). These effects were reversed by SR144528. CBD and ACEA were not neuroprotective. |
Palazuelos et al. [35] | Mice expressing mHTT or quinolinic acid exposure |
| HU-308 reduced quinolinic acid neurotoxicity. |
Sotter et al. [34] | Pheochromocytoma cells expressing mHHT |
| HU210 caused small, but significant increase of cell survival. It excerted potentially toxic effects including increased huntingtin aggregation. |
Dowie et al. [37] | R6/1 transgenic mice |
| HU210 and THC did not improve motor symptoms. HU210 treatment was associated with seizures. |
Valdeolivas S et al. [27] | Malonate rats |
| THC/CBD was neuroprotective. SR141716 and AM630 reduced its neuroprotective effects |
Studies investigating the relevance of endocannabinoid system in HD pathogenesis in animal models. Studies are presented in chronological order.
HD: Huntington disease; CB1R: cannabinoid receptor type 1; CB2R: cannabinoid receptor type 2; 3 NP mice: 3-nitropropionic acid; eCBRI: endocannabinoid re-uptake inhibitor; TRPV1: the transient receptor potential cation channel subfamily V member 1
The post-mortem examination of brain tissue in individuals with HD as well as PET imaging studies
First reports of using cannabinoids in patients with HD were contradictory [24, 28, 30]. In 1991, Consroe et al. conducted the first double-blind randomized cross-over study to evaluate the efficacy and safety of oral CBD (10 mg/kg/day for 6 weeks) in 15 neuroleptic-free patients with HD [28]. The therapeutic response was evaluated with the use of the Marsden and Quinn chorea severity scale [40]. In this study, no statistically significant improvement has been shown. There was also no significant difference between the CBD and placebo groups in terms of side effects. In 1999 Müller-Vahl et al. published a case of a 58-year-old male with HD who was treated with a single dose of 1.5 mg of a CB1 agonist, nabilone. In this individual, a severe deterioration of chorea was observed [24]. In 2006, Curtis et al. described a case of a 43-year-old female, whose chorea and irritability improved after medication with 1 mg of nabilone [30]. A double-blind placebo-controlled randomized cross-over trial using nabilone was conducted in 2009 by the same author. This time 37 patients were treated with 1 mg or 2 mg of nabilone daily for 5 weeks. For primary measures, the patients were assessed with Unified Huntington’s Disease Rating Scale (UHDRS) total motor score and UHDRS subsections for chorea, cognition and behavior, and neuropsychiatric inventory (NPI) for secondary measures. There were no statistically significant differences in total UHDRS between the groups. However, statistically, significant improvements were noted for the UHDRS chorea scale and the neuropsychiatric inventory. There were no statistical differences reported between the 1 and 2 mg. Adverse effects were reported for placebo and nabilone similarly. There was one Serious Adverse Event (SAE) related to nabilone—one of the patients withdrew due to severe sedation. Importantly, no psychoses were reported [23]. In 2016, the results of a study conducted by Moreno et al. using nabiximols in the treatment of HD were published [36]. Nabiximols (tradename
An overview of all available studies investigating the efficacy and safety of CBM in HD is provided in Table 2.
Reference | Number of patients (sex) | Age (mean) | Substance | Study design | Outcome |
---|---|---|---|---|---|
Consroe et al. [41] | 15 (8 male, 7 female) | No data | CBD | Double-blind, randomized cross-over study | No significant improvement No relevant side effects |
Müller-Vahl et al. [42] | 1 male | 58 | Nabilone | Case report | Deterioration of chorea |
Curtis et al. [43] | 1 female | 43 | Nabilone | Case report | Improvement of chorea and irritability |
Curtis et al. [44] | 44 (22 male, 22 female) | 52 | Nabilone | Double-blind, placebo-controlled, cross-over study | Improvement of the UHDRS-chorea; 1 SAE – sedation |
Moreno et al. [45] | 25 (14 male, 11 female) | 47.6 | Nabiximols | Double-blind, randomized, cross-over, placebo-controlled, pilot trial | No SAE or clinical worsening; no significant improvement; no significant changes of biomarkers |
An overview of studies investigating efficacy and safety of CBM in HD.
CBM: cannabis based medicine; HD: Huntington disease; SAE: severe adverse events; CBD: cannabidiol; UHDRS: United Huntington Disease Rating Scale; and SAE: serious adverse events.
Even today, very little is known about the safety of CBM in patients with HD due to the limited number of studies exploring this issue. However, the available preliminary results suggest that the safety profile of CBM in HD is similar to that in other groups of patients. A recently conducted meta-analysis, including diverse populations of patients treated with CBM, showed that administration of cannabinoids can be associated with a greater risk of adverse events (AE), including serious adverse events (SAE) [46]. The most common short-term AEs included dizziness, dry mouth, nausea or vomiting, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucinations. So far, there has been no study evaluating the long-term AEs of cannabinoids [46]. Up to this point, only two CBM-related SAEs in HD have been reported and both occurred after the treatment with nabilone. A 58-year-old male described by Müller-Vahl experienced an exacerbation of chorea. Moreover, the patient noticed the deterioration of short-term memory [42]. During the study performed by Curtis et al. [44], one of the patients experienced severe sedation and had to withdraw from the trial. Importantly, none of the patients enrolled in this study suffered from exacerbation of chorea or psychosis. The most frequent AE was drowsiness and forgetfulness. In the recent study conducted by Moreno et al. [45], dizziness or disturbance in attention were the two most common AEs. No serious alterations in psychiatric or neurological conditions of the participants were noted [45].
There is increasing evidence that the endocannabinoid system is a new promising therapeutical target in patients with HD. However, larger well-designed controlled studies are urgently needed to confirm the efficacy and safety of this treatment.
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It is a leading cause of disability in children. Congenitally infected neonates often appear asymptomatic at birth or have nonspecific symptoms. An early diagnosis and subsequent early antiviral therapy associated to nonpharmacological therapy (e.g., hearing rehabilitation, speech-language therapy, and cochlear implants) can reduce long-term disability. Much research has been done in this field, but further studies are still necessary. Looking back at the most recent papers, we will draw a review on this topic trying to answer to the question: could universal CMV screening be a useful and cost-effective diagnostic tool?",book:{id:"8728",slug:"update-on-critical-issues-on-infant-and-neonatal-care",title:"Update on Critical Issues on Infant and Neonatal Care",fullTitle:"Update on Critical Issues on Infant and Neonatal Care"},signatures:"Sara Lunardi, Francesca Lorenzoni and Paolo Ghirri",authors:null},{id:"44446",doi:"10.5772/54310",title:"Neonatal Pneumonia",slug:"neonatal-pneumonia",totalDownloads:14749,totalCrossrefCites:1,totalDimensionsCites:5,abstract:null,book:{id:"2990",slug:"neonatal-bacterial-infection",title:"Neonatal Bacterial Infection",fullTitle:"Neonatal Bacterial Infection"},signatures:"Friedrich Reiterer",authors:[{id:"152025",title:"Prof.",name:"Friedrich",middleName:null,surname:"Reiterer",slug:"friedrich-reiterer",fullName:"Friedrich Reiterer"}]},{id:"38034",doi:"10.5772/34698",title:"Maternal Socio-economic Status and Childhood Birth weight: A Health Survey in Ghana.",slug:"maternal-socio-economic-status-and-childhood-birth-weight-a-health-survey-in-ghana-",totalDownloads:3608,totalCrossrefCites:2,totalDimensionsCites:3,abstract:null,book:{id:"741",slug:"neonatal-care",title:"Neonatal Care",fullTitle:"Neonatal Care"},signatures:"Edward Nketiah-Amponsah, Aaron Abuosi and Eric Arthur",authors:[{id:"101268",title:"Dr.",name:"Edward",middleName:null,surname:"Nketiah-Amponsah",slug:"edward-nketiah-amponsah",fullName:"Edward Nketiah-Amponsah"}]}],mostDownloadedChaptersLast30Days:[{id:"44446",title:"Neonatal Pneumonia",slug:"neonatal-pneumonia",totalDownloads:14749,totalCrossrefCites:1,totalDimensionsCites:5,abstract:null,book:{id:"2990",slug:"neonatal-bacterial-infection",title:"Neonatal Bacterial Infection",fullTitle:"Neonatal Bacterial Infection"},signatures:"Friedrich Reiterer",authors:[{id:"152025",title:"Prof.",name:"Friedrich",middleName:null,surname:"Reiterer",slug:"friedrich-reiterer",fullName:"Friedrich Reiterer"}]},{id:"53683",title:"Pre and Postoperative Management of Pediatric Patients with Congenital Heart Diseases",slug:"pre-and-postoperative-management-of-pediatric-patients-with-congenital-heart-diseases",totalDownloads:4889,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Stabilization during preoperative cardiac surgery especially in neonates has an important role to predict outcome for pediatric congenital heart surgery. We tried to elaborate general guidelines on how to diagnose and some anticipations for emergency treatments tailored by the type of congenital heart disease in neonates. Stabilization consists of medical treatment including emergent prostaglandin institution in some types of duct dependent lesion. The role of interventional catheterization such as patent ductus arteriosus (PDA) stent, balloon pulmonary valvotomy, etc. as modalities for stabilization before surgery was also elaborated. Some general and specific guidelines based on the type of surgeries for postoperative management were also discussed.",book:{id:"5473",slug:"pediatric-and-neonatal-surgery",title:"Pediatric and Neonatal Surgery",fullTitle:"Pediatric and Neonatal Surgery"},signatures:"Eva Miranda Marwali, Beatrice Heineking and Nikolaus A. 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It is more common during the neonatal period than at any other age with the estimated incidence of 0.25 per 1000 live births. The absence of specific clinical presentation makes diagnosis of meningitis more difficult in neonates than in older children. Culture of cerebrospinal fluid is the traditional gold standard for diagnosis of bacterial meningitis, so all newborn infants with proven or suspected sepsis should undergo lumbar puncture. However, deciding when to perform lumbar puncture and interpretation of the results are challenging. Although the pathophysiology of neonatal meningitis is complex and not fully understood, researches on diagnostic and prognostic tools are ongoing. Prevention of neonatal sepsis, early recognition of infants at risk, development of novel, rapid diagnostics and adjunctive therapies, and appropriate and aggressive antimicrobial treatment to sterilize cerebrospinal fluid as soon as possible may prevent the lifelong squeal of bacterial meningitis in newborn infants.",book:{id:"7527",slug:"neonatal-medicine",title:"Neonatal Medicine",fullTitle:"Neonatal Medicine"},signatures:"Mehmet Şah İpek",authors:[{id:"267903",title:"Associate Prof.",name:"Mehmet Şah",middleName:null,surname:"İpek",slug:"mehmet-sah-ipek",fullName:"Mehmet Şah İpek"}]},{id:"71427",title:"Factors Influencing Maternal Decision-Making on Infant Feeding Practices",slug:"factors-influencing-maternal-decision-making-on-infant-feeding-practices",totalDownloads:984,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The decision to formula feed or breastfeed a child typically begins with an established prenatal intention. 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