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Background: Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others. Methods: In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies. Results: Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis. Current treatments ameliorate the symptoms but are not curative. Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration. To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.
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... Endocannabinoid system (ECS) plays role in many physiological processes, including mood, learning and memory. It is also involved in the pathogenesis of anxiety and mood disorders, as well as neurodegenerative disorders (Hill and Gorzalka, 2009;Ranieri et al., 2016). ECS consists of the endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes that synthesize and degrade endocannabinoids. ...
... There is an intensive research on modulation of the components of ECS in attempt to develop pharmacological therapy for treatment of anxiety and depressive disorders. Studies also have provided evidence that the ECS has neuro-protective properties and might be a target in neurodegenerative diseases (Ranieri et al., 2016). ...
Article
The brain endocannabinoid system has been shown to play a role in many physiological processes, including mood, learning and memory. It is also involved in the pathogenesis of anxiety, depression, mood disorders, as well as neurodegenerative disorders, although the exact mechanisms by which cannabinoid receptors interfere in these disorders are not well established. The aim of the present study was to evaluate the effects of cannabinoid ligands HU‑210 (CB1 receptor agonist) and SR 141716A (CB1 receptor antagonist) on learning and memory processes of rats with depressive - like state, induced by bilateral olfactory bulbectomy. The bilateral olfactory bulbectomy (OBX) is a validated model of depression, which can be used also as an animal model of Alzheimer's disease. We found that the subchronic treatment of OBX rats with HU 210 and SR 141716A exerted modulatory effect on rat's performance in both active avoidance (shuttle box) and passive avoidance (step through) tests. HU 210 ameliorated the memory deficits of OBX rats; however, the scores of the sham‑operated controls had not been reached. SR 141716A modified the avoidance performance in OBX rats and showed a memory enhancing effect in the sham‑operated rats. Our findings suggest that CB1 receptors might be involved in avoidance learning and memory acquisition in OBX rats.
... Several animal models and human studies have demonstrated that the ECS significantly influences the development of neuroinflammation and the progression of brain injury and neurodegenerative diseases [1][2][3]. Using a model of cerebral focal ischemia, it was shown that exogenously administered AEA and 2-AG in combination reduced infarct size in rats, but with no facilitatory effects beyond AEA or 2-AG alone [202]. Other studies reported neuroprotective effects of exogenous AEA [203] and 2-AG [56] under traumatic brain injury (TBI). ...
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Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB1/2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-α and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.
... These conditions probably may also be caused by dysregulations that occur in the endocannabinoid signaling pathway. The background of these disturbances seems to be very complex and includes altered cannabinoid receptors signaling and expression as well as fluctuations in endocannabinoid concentrations in serum [70,71]. ...
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The worldwide prevalence of neurological and neurodegenerative disorders, such as depression or Alzheimer’s disease, has spread extensively throughout the last decades, becoming an enormous health issue. Numerous data indicate a distinct correlation between the altered endocannabinoid signaling and different aspects of brain physiology, such as memory or neurogenesis. Moreover, the endocannabinoid system is widely regarded as a crucial factor in the development of neuropathologies. Thus, targeting those disorders via synthetic cannabinoids, as well as phytocannabinoids, becomes a widespread research issue. Over the last decade, the endocannabinoid system has been extensively studied for its correlation with physical activity. Recent data showed that physical activity correlates with elevated endocannabinoid serum concentrations and increased cannabinoid receptor type 1 (CB1R) expression in the brain, which results in positive neurological effects including antidepressant effect, ameliorated memory, neuroplasticity development, and reduced neuroinflammation. However, none of the prior reviews presented a comprehensive correlation between physical activity, the endocannabinoid system, and neuropathologies. Thus, our review provides a current state of knowledge of the endocannabinoid system, its action in physical activity, as well as neuropathologies and a possible correlation between all those fields. We believe that this might contribute to finding a new preventive and therapeutic approach to both neurological and neurodegenerative disorders.
... e ECS is a system of enzymes (that control the production and degradation of endogenous cannabinoids), cannabinoid receptors (CB1R and CB2R), and molecules that interact with these receptors. Cannabinoid receptors type 1 (CB1R) are predominantly expressed in the central nervous system (CNS), making them a potential target for neuropsychological disorders and neurodegenerative diseases [4][5][6]. e primary drawback to molecules that bind to CB1R is their psychoactive potential, which may limit therapeutic use [7]. Indeed, activation of CB1R may, in some cases, precipitate episodes of psychosis and panic [7]. ...
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Aromatic compounds have a long history of use as medicines in most recorded cultures. An increasing interest in these therapeutic volatile molecules in both scientific and lay communities has led to the advancement of essential oils as phytomedicines. Recent discoveries suggest essential oils augment the endocannabinoid system in a positive manner to mitigate various pathologies. However, the exact mechanisms whereby essential oils influence endocannabinoid system activity are not fully known, these studies provide a glimpse into their involvement and warrant further evaluation. Additional study of the interaction between essential oils and the endocannabinoid system may lead to promising phytomedicines for the treatment of diseases and conditions involving dysregulation or activation of the endocannabinoid system.
... The endocannabinoid system comprises the cannabinoid receptors 1 and 2 (CB1 and CB2, respectively); the receptors for AEA and 2-AG, respectively; and the enzymes involved in synthesis and degradation of endocannabinoids [1] . Studies have confirmed the endocannabinoid system to be closely related to the development of irritable bowel syndrome (IBS), nervous system diseases, cardiovascular disease, pain, inflammation and tumors [2][3][4][5][6] ; thus, the components of the endocannabinoid system represent 3 potential therapeutic targets to treat these diseases. ...
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Background: The endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid, which is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL). The present study aimed to explore the effects of inhibition of MAGL on intestinal permeability. Methods: We first tested it in differentiated CaCO2 cells after 21 days’ culture. The rat model of water avoidance stress (WAS) was established, and rats were divided into four groups according to intervention. Rats received intraperitoneal injection (i.p.) of an MAGL inhibitor (JZL184) alone, JZL184 and the cannabinoid receptor 1 (CB1) antagonist (SR141716A), JZL184 and a cannabinoid receptor 2 (CB2) antagonist (AM630) or vehicle alone (control). We analyzed the fluorescein isothiocyanate-dextran (FD4) permeability and 2-AG level. Expression of MAGL and tight-junction-associated proteins were detected by western blot. Results: Compared with the control group, MAGL expression was higher and 2-AG levels lower among WAS rats. Intestinal permeability was increased following administration of JZL184 which occurred due to up-regulation of tight-junction-associated proteins Claudin-1, Claudin-2, Claudin-5 and Occludin. Conclusion: The effects of MAGL inhibition were mediated by CB1, indicating that MAGL may represent a novel target for the treatment of reduced intestinal permeability in the context of chronic stress.
... Specifically, the CBD product Epidiolex was recently approved for the treatment of refractory epilepsies like Lennox-Gastaut syndrome and Dravet syndrome. 4 In addition to phytocannabinoids, many synthetic cannabinoids (SCs) have been produced through various drug development pipelines to target the endogenous cannabinoid system (ECS). 5 Initially developed and evaluated as research tools, these lead SCs were not intended for human consumption. ...
Article
Cannabinoids are compounds that are structurally and/or functionally related to the primary psychoactive constituent of Cannabis sativa, [INCREMENT]-tetrahydrocannabinol (THC). Cannabinoids can be divided into three broad categories: endogenous cannabinoids, plant-derived cannabinoids, and synthetic cannabinoids (SCs). Recently, there has been an unprecedented surge of interest into the pharmacological and medicinal properties of cannabinoids for the treatment of epilepsies. This surge has been stimulated by an ongoing shift in societal opinions about cannabinoid-based medicines and evidence that cannabidiol, a nonintoxicating plant cannabinoid, has demonstrable anticonvulsant activity in children with treatment-refractory epilepsy. The major receptors of the endogenous cannabinoid system (ECS)-the type 1 and 2 cannabinoid receptors (CB1R, CB2R)-have critical roles in the modulation of neurotransmitter release and inflammation, respectively; so, it is not surprising therefore that the ECS is being considered as a target for the treatment of epilepsy. SCs were developed as potential new drug candidates and tool compounds for studying the ECS. Beyond the plant cannabinoids, an extensive research effort is underway to determine whether SCs that directly target CB1R, CB2R, or the enzymes that breakdown endogenous cannabinoids have anticonvulsant effects in preclinical rodent models of epilepsy and seizure. This research demonstrates that many SCs do reduce seizure severity in rodent models and may have both positive and negative pharmacodynamic and pharmacokinetic interactions with clinically used antiepilepsy drugs. Here, we provide a comprehensive review of the preclinical evidence for and against SC modulation of seizure and discuss the important questions that need to be addressed in future studies.
Article
Background: Preclinical and clinical evidence suggests a role for the dysregulation of the endocannabinoid system in migraine pain, particularly in subjects with chronic migraine. Methods: The gene expression of endocannabinoid system components was assayed in peripheral blood mononuclear cells of 25 subjects with episodic migraine, 26 subjects with chronic migraine with medication overuse (CM-MO) and 24 age-matched healthy controls. We also evaluated the protein expression of cannabinoid receptors 1 and 2 as well as DNA methylation changes in genes involved in endocannabinoid system components. Results: Both episodic migraine and CM-MO subjects showed higher cannabinoid receptor 1 and cannabinoid receptor 2 gene and protein expression compared to controls. Fatty acid amide hydrolase gene expression, involved in anandamide degradation, was lower in migraine groups compared to healthy control subjects. N-arachidonoyl phosphatidylethanolamine phospholipase D gene expression was significantly higher in all migraineurs, as were monoacylglycerol lipase and diacylglycerol lipase gene expressions. The above markers significantly correlated with the number of migraine days and with the days of acute drug intake. Conclusion: The findings point to transcriptional changes in endocannabinoid system components occurring in migraineurs. These changes were detected peripherally, which make them amenable for a wider adoption to further investigate their role and applicability in the clinical field.clinicaltrials.gov NTC04324710.
Article
Background Alcohol use disorders affect millions of people worldwide and there is growing evidence that excessive alcohol intake causes severe damage to the brain of both humans and animals. Numerous studies on chronic alcohol exposure in animal models have identified that many functional impairments are associated with the hippocampus, which is a structure exhibiting substantial vulnerability to alcohol exposure. However, the precise mechanisms that lead to structural and functional impairments of the hippocampus are poorly understood. Herein, we report a novel cell death type, namely pyroptosis, which accounts for alcohol neurotoxicity in mice. Methods For this study, we used an in viv o model to induce alcohol‐related neurotoxicity in the hippocampus. Adult male C57BL/6 mice were treated with 95% alcohol vapor either alone or in combination with selective cannabinoid receptor antagonists or agonists as well as VX765 (Belnacasan), which is a selective caspase‐1 inhibitor. Results Alcohol‐induced in vivo pyroptosis occurs because of an increase in the levels of pyroptotic proteins such as nucleotide‐binding domain (NOD)‐like receptor protein 3 (NLRP3), caspase‐1, gasdermin‐D (GSDMD), and amplified inflammatory response. Our results indicated that VX765 suppressed the expression of caspase‐1 and inhibited the maturation of the proinflammatory cytokines Interleukin ‐1β (IL‐1β) and IL‐18. Additionally, chronic alcohol intake created an imbalance in the endocannabinoid system and regulated two cannabinoid receptors (CB1R and CB2R) in the hippocampus. Specific antagonists of CB1R (AM251 and AM281) significantly ameliorated alcohol‐induced pyroptosis signaling and inactivated the inflammatory response. Conclusions Alcohol induces hippocampal pyroptosis, which leads to neurotoxicity thereby indicating that pyroptosis may be an essential pathway involved in chronic alcohol‐induced hippocampal neurotoxicity. Further, cannabinoid receptors are regulated during this process, which suggests promising therapeutic strategies against alcohol‐induced neurotoxicity through pharmacologic inhibition of CB1R.
Article
The endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid, which is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL). The present study aimed to explore the effects of inhibition of MAGL on intestinal permeability. We first tested it in differentiated CaCO2 cells after 21 days’ culture. The rat model of water avoidance stress (WAS) was established, and rats were divided into four groups according to intervention. Rats received intraperitoneal injection (i.p.) of an MAGL inhibitor (JZL184) alone, JZL184 and a the cannabinoid receptor 1 (CB1) receptor antagonist (SR141716A), JZL184 and a cannabinoid receptor 2 (CB2) receptor antagonist (AM630) or vehicle alone (control). We analyzed the fluorescein isothiocyanate-dextran (FD4) permeability and 2-AG level. Expression of MAGL and tight-junction-associated proteins were detected by western blot. Compared with the control group, MAGL expression was higher and 2-AG levels lower among WAS rats. Intestinal permeability was increased following administration of JZL184 which occurred due to up-regulation of tight-junction-associated proteins Claudin-1, Claudin-2, Claudin-5 and Occludin. The effects of MAGL inhibition were mediated by CB1, indicating that MAGL may represent a novel target for the treatment of reduced intestinal permeability in the context of chronic stress.
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Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).
Article
Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system. Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Post-symptom treatment with an ABHD6 inhibitor WWL70 increased the brain levels of 2-AG and ameliorated the clinical signs of EAE, T cells infiltration, microglia activation and the expression of activated leukocyte cell adhesion molecules. The production of iNOS, COX-2, TNF-α and IL-1β and the phosphorylation of NF-κB were also significantly reduced by WWL70 treatment. The neuroprotective effect of WWL70 was demonstrated by increased survival of mature oligodendrocytes, reduced demyelination and axonal loss in WWL70 treated EAE mouse spinal cord. The therapeutic effect of WWL70 on EAE was absent by co-administration of CB2 receptor antagonist, but not CB1 receptor antagonist. Consistently, WWL70 did not afford any protection in CB2 receptor knockout mice after EAE induction. Given the increased expression of ABHD6 in microglia/macrophages, but not in T cells, we speculated that inhibition of ABHD6 might enhance 2-AG signaling particularly in microglia/macrophages to exert anti-inflammatory effects via activation of CB2 receptors. These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases. Copyright © 2015. Published by Elsevier Ltd.
Article
Growing evidence suggests that the endocannabinoid system is involved in the pathogenesis of Alzheimer's disease (AD) and atherosclerosis. The purpose of this study was to investigate the activation of the endocannabinoid system in AD in vivo and the possible intermediate role of atherosclerosis. We enrolled 41 patients with probable AD, and 30 age- and gender-matched controls. All subjects underwent: ultrasound examination of cerebral and neck vessels (including intima-media thickness and plaque stenosis evaluation); blood sampling to measure levels of endocannabinoid [anandamide (AEA), 2-arachidonoylglycerol (2-AG)] and endogenous AEA analogues [N-palmitoyl-ethanolamide (PEA); N-oleoyl-ethanolamide]; neuropsychological evaluation and brain MRI (atrophy, white matter hyperintensity volume). 2-AG levels were higher in AD patients compared to controls (Mann-Whitney test p = 0.021). In the AD group, 2-AG correlated to white matter hyperintensity volume (r = 0.415, p = 0.015) and was higher in patients with chronic heart ischemic disease (p = 0.023). In AD patients, 2-AG was also positively related to memory (r = 0.334, p = 0.05) and attention (r = 0.423, p = 0.018) performances. Constructional praxia test scores were lower in patients with higher levels of PEA (r = -0.389, p = 0.019). AD patients present high plasma 2-AG levels, also in relation to heart ischemic disease and cerebral leukoaraiosis. This may be a protective mechanism hindering neurodegeneration, but it may also play an ambivalent role on cerebrovascular circulation. The increase in 2-AG and PEA levels observed with ongoing pathological processes may differently modulate cognitive performances.