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The endocannabinoid system (ECS) consists of a variety of long-chain unsaturated fatty acid analogs, mainly anandamide (AEA) and 2-arachidoniyl glycerol (2-AG), along with their specific binding G protein-coupled receptors, cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). It affects the life process and biological activity of almost all cells in the body by influencing cell material and energy metabolism. In the liver, the physiological expression of ECS is at a low level. The expression and secretion of ECS in the liver can be strongly stimulated by liver injury factors. ECS acts as a trigger in multiple liver diseases. It is known to be related to the process of hepatocyte steatosis and promote the formation and development of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). It is involved in the inflammatory processes of liver diseases and greatly affects the immune-inflammatory response in liver tissue. It is also involved in the formation of liver fibers and promotes the occurrence and development of liver fibrosis and cirrhosis. Finally, the role and mechanisms of ECS in the occurrence and development of liver diseases are elaborated in detail by listing lipid metabolism-related liver diseases (NAFLD and ALD) and other liver diseases.

Stress provokes stress-induced analgesia (SIA), which depends on an opioid and non-opioid components. The non-opioid one comprises several systems among which are endocannabinoid (ECS), adrenergic, and nitricoxidergic participating in the descending antinociceptive system of the body. The ECS system has a well-established role in the modulation of pain perception and behavioral responses after stress. Nociceptin/Orphanin FQ(N/OFQ) is a heptadecapeptide that has been found to play a role in pain perception. This study aimed to investigate the effects of novel nociceptin N/OFQ(1-13)NH2 analogues on nociception after chronic immobilization stress (CIS) and the involvement of the ECS in analgesic effects. The experiments were carried out on male Wistar rats. The animals were immobilized in a tube for 3 hours daily for 4 days. Analgesic effects were examined by the paw-pressure (PP) test. All novel analogues of N/OFQ(1-13) NH2, the cannabinoid receptor type 1 (CB1-receptor) agonist N-arachidonoylethanolamide (AEA), and the CB1-receptors antagonist N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) were administered intraperitoneally (i.p) dissolved in Dimethyl sulfoxide (DMSO). Statistical analysis was performed using one-way ANOVA. The results showed that nociceptin and analogues administered after CIS decreased the pain threshold significantly compared to a group that underwent chronic stress only. The administration of AEA immediately after the end of stress led to a significantly increased pain threshold, while administration of AM251 significantly decreased the pain threshold versus the both control and group that underwent chronic stress only. Nociceptin and analogues co-administered with CB1-receptor agonist (AEA) or antagonist (AM251) after the end of stress decreased immobilization SIA. Our study gives us reason to assume the participation of ECS in the analgesic effects of the novel nociceptin analogues after chronic immobilization stress. [ABSTRACT FROM AUTHOR]

Diet-induced obesity (DIO) is a contributor to co-morbidities, resulting in alterations in hormones, lipids, and low-grade inflammation, with the cannabinoid type 2 receptor (CB2) contributing to the inflammatory response. The effects of modulating CB2 with pharmacological treatments on inflammation and adaptations to the obese state are not known. Therefore, we aimed to investigate the molecular mechanisms in adipose tissue of CB2 agonism and CB2 antagonism treatment in a DIO model. Male Sprague Dawley rats were placed on a high-fat diet (HFD) (21% fat) for 9 weeks, then received daily intraperitoneal injections with a vehicle, AM630 (0.3 mg/kg), or AM1241 (3 mg/kg), for a further 6 weeks. AM630 or AM1241 treatment in DIO rats did not alter their body weight, food intake, or liver weight, and it had no effect on their numerous circulating cytokines or peri-renal fat pad mass. AM1241 decreased heart weight and BAT weight; both treatments (AM630 or AM1241) decreased plasma leptin levels, while AM630 also decreased plasma ghrelin and GLP-1 levels. Both treatments decreased Adrb3 and TNF-α mRNA levels in eWAT and TNF-α levels in pWAT. AM630 treatment also decreased the mRNA levels of Cnr2, leptin, and Slc2a4 in eWAT. In BAT, both treatments decreased leptin, UCP1, and Slc2a4 mRNA levels, with AM1241 also decreasing Adrb3, IL1β, and PRDM16 mRNA levels, and AM630 increasing IL6 mRNA levels. In DIO, CB2 agonist and CB2 antagonist treatment reduces circulating leptin in the absence of weight loss and modulates the mRNA responsible for thermogenesis. [ABSTRACT FROM AUTHOR]

The endocannabinoid system (ECS) is a widespread modulatory system composed of cannabinoid receptors, endogenous signaling lipids termed endocannabinoids and the enzymes for the biosynthesis and degradation of these endocannabinoids. It plays a crucial role in diverse (patho)physiological functions, such as neurotransmission, neural development, synaptic plasticity, mood, food intake, and inflammation. Enzymes involved in the biosynthesis (e. g. NAPE‐PLD, DAGLs) and degradation (e. g. FAAH, MAGL) of endocannabinoids have attracted attention from both academia and industry due to their therapeutic potential. The discovery of selective inhibitors for these enzymes is important for functional assignment and biomedical applications. Activity‐based protein profiling (ABPP) has emerged as a powerful technique, which to a large extend accelerated the development of selective inhibitors for ECS enzymes. This review summarizes the representative activity‐based probes (ABPs) and small molecular inhibitors developed in the past two decades for ECS enzymes and will discuss the biological discoveries attributed by the application of these small molecules. [ABSTRACT FROM AUTHOR]

The endocannabinoid system (ECS) refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Cannabinoid receptors (CBRs) are highly expressed in the central nervous system and many peripheral tissues. Evidence suggests that CB1Rs are expressed in human and murine skeletal muscle mainly in the cell membrane, but a subpopulation is present also in the mitochondria. However, very little is known about the latter population. To date, the connection between the function of CB1Rs and the regulation of intracellular Ca2+ signaling has not been investigated yet. Tamoxifen-inducible skeletal muscle-specific conditional CB1 knock-down (skmCB1-KD, hereafter referred to as Cre+/−) mice were used in this study for functional and morphological analysis. After confirming CB1R down-regulation on the mRNA and protein level, we performed in vitro muscle force measurements and found that peak twitch, tetanus, and fatigue were decreased significantly in Cre+/− mice. Resting intracellular calcium concentration, voltage dependence of the calcium transients as well as the activity dependent mitochondrial calcium uptake were essentially unaltered by Cnr1 gene manipulation. Nevertheless, we found striking differences in the ultrastructural architecture of the mitochondrial network of muscle tissue from the Cre+/− mice. Our results suggest a role of CB1Rs in maintaining physiological muscle function and morphology. Targeting ECS could be a potential tool in certain diseases, including muscular dystrophies where increased endocannabinoid levels have already been described. [ABSTRACT FROM AUTHOR]

Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a "browning" of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders. [ABSTRACT FROM AUTHOR]

Background: The prevalence of cannabis use and cannabis use disorders (CUD) has significantly increased over time. However, there are no approved pharmacological treatments for CUD. The aim of this study was to determine the efficacy and safety of various medical cannabinoids in the treatment of CUD. Methods: We conducted a systematic review of randomized controlled trials which evaluated the therapeutic potential of medical cannabinoids in individuals with CUD and summarized the main study outcomes in terms of cannabis use, abstinence, withdrawal symptoms, craving, retention in treatment and adverse events. Results: We identified eight trials with a total of 667 study participants. Dronabinol reduced cannabis withdrawal symptoms whereas nabiximols, cannabidiol and PF-04457845, a fatty acid amide inhibitor, also reduced cannabis use and improved abstinence, compared to placebo. Nabilone failed to demonstrate efficacy in the treatment of CUD. All medications were well-tolerated. Conclusions: Cannabinoid receptor agonists, i.e., dronabinol and nabilone, showed only limited or no therapeutic potential in the treatment of CUD. In contrast, modulators of endocannabinoid activity, i.e., nabiximols, cannabidiol and PF-04457845, demonstrated broader efficacy which covered almost all aspects of CUD. Endocannabinoid modulation appears to be a promising treatment approach in CUD, but the evidence to support this strategy is still small and future research in this direction is needed. [ABSTRACT FROM AUTHOR]

BackgroundThe prevalence of cannabis use and cannabis use disorders (CUD) has significantly increased over time. However, there are no approved pharmacological treatments for CUD. The aim of this study was to determine the efficacy and safety of various medical cannabinoids in the treatment of CUD.MethodsWe conducted a systematic review of randomized controlled trials which evaluated the therapeutic potential of medical cannabinoids in individuals with CUD and summarized the main study outcomes in terms of cannabis use, abstinence, withdrawal symptoms, craving, retention in treatment and adverse events.ResultsWe identified eight trials with a total of 667 study participants. Dronabinol reduced cannabis withdrawal symptoms whereas nabiximols, cannabidiol and PF-04457845, a fatty acid amide inhibitor, also reduced cannabis use and improved abstinence, compared to placebo. Nabilone failed to demonstrate efficacy in the treatment of CUD. All medications were well-tolerated.ConclusionsCannabinoid receptor agonists, i.e., dronabinol and nabilone, showed only limited or no therapeutic potential in the treatment of CUD. In contrast, modulators of endocannabinoid activity, i.e., nabiximols, cannabidiol and PF-04457845, demonstrated broader efficacy which covered almost all aspects of CUD. Endocannabinoid modulation appears to be a promising treatment approach in CUD, but the evidence to support this strategy is still small and future research in this direction is needed.

Diet-induced obesity (DIO) is a contributor to co-morbidities, resulting in alterations in hormones, lipids, and low-grade inflammation, with the cannabinoid type 2 receptor (CB2) contributing to the inflammatory response. The effects of modulating CB2 with pharmacological treatments on inflammation and adaptations to the obese state are not known. Therefore, we aimed to investigate the molecular mechanisms in adipose tissue of CB2 agonism and CB2 antagonism treatment in a DIO model. Male Sprague Dawley rats were placed on a high-fat diet (HFD) (21% fat) for 9 weeks, then received daily intraperitoneal injections with a vehicle, AM630 (0.3 mg/kg), or AM1241 (3 mg/kg), for a further 6 weeks. AM630 or AM1241 treatment in DIO rats did not alter their body weight, food intake, or liver weight, and it had no effect on their numerous circulating cytokines or peri-renal fat pad mass. AM1241 decreased heart weight and BAT weight; both treatments (AM630 or AM1241) decreased plasma leptin levels, while AM630 also decreased plasma ghrelin and GLP-1 levels. Both treatments decreased Adrb3 and TNF-α mRNA levels in eWAT and TNF-α levels in pWAT. AM630 treatment also decreased the mRNA levels of Cnr2, leptin, and Slc2a4 in eWAT. In BAT, both treatments decreased leptin, UCP1, and Slc2a4 mRNA levels, with AM1241 also decreasing Adrb3, IL1β, and PRDM16 mRNA levels, and AM630 increasing IL6 mRNA levels. In DIO, CB2 agonist and CB2 antagonist treatment reduces circulating leptin in the absence of weight loss and modulates the mRNA responsible for thermogenesis.

Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide. Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders. In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer's disease, Parkinson's disease and Multiple Sclerosis's patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system. In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines. [ABSTRACT FROM AUTHOR]

In late 2019, COVID-19 emerged in Wuhan, China. Currently, it is an ongoing global health threat stressing the need for therapeutic compounds. Linking the virus life cycle and its interaction with cell receptors and internal cellular machinery is key to developing therapies based on the control of infectivity and inflammation. In this framework, we evaluate the combination of cannabidiol (CBD), as an anti-inflammatory molecule, and terpenes, by their anti-microbiological properties, in reducing SARS-CoV-2 infectivity. Our group settled six formulations combining CBD and terpenes purified from Cannabis sativa L, Origanum vulgare , and Thymus mastichina. The formulations were analyzed by HPLC and GC-MS and evaluated for virucide and antiviral potential by in vitro studies in alveolar basal epithelial, colon, kidney, and keratinocyte human cell lines. Conclusions and Impact: We demonstrate the virucide effectiveness of CBD and terpene-based formulations. F2TC reduces the infectivity by 17%, 24%, and 99% for CaCo-2, HaCat, and A549, respectively, and F1TC by 43%, 37%, and 29% for Hek293T, HaCaT, and Caco-2, respectively. To the best of our knowledge, this is the first approach that tackles the combination of CBD with a specific group of terpenes against SARS-CoV-2 in different cell lines. The differential effectiveness of formulations according to the cell line can be relevant to understanding the pattern of virus infectivity and the host inflammation response, and lead to new therapeutic strategies. [ABSTRACT FROM AUTHOR]

In late 2019, COVID-19 emerged in Wuhan, China. Currently, it is an ongoing global health threat stressing the need for therapeutic compounds. Linking the virus life cycle and its interaction with cell receptors and internal cellular machinery is key to developing therapies based on the control of infectivity and inflammation. In this framework, we evaluate the combination of cannabidiol (CBD), as an anti-inflammatory molecule, and terpenes, by their anti-microbiological properties, in reducing SARS-CoV-2 infectivity. Our group settled six formulations combining CBD and terpenes purified from Cannabis sativa L, Origanum vulgare, and Thymus mastichina. The formulations were analyzed by HPLC and GC-MS and evaluated for virucide and antiviral potential by in vitro studies in alveolar basal epithelial, colon, kidney, and keratinocyte human cell lines.Conclusions and ImpactWe demonstrate the virucide effectiveness of CBD and terpene-based formulations. F2TC reduces the infectivity by 17%, 24%, and 99% for CaCo-2, HaCat, and A549, respectively, and F1TC by 43%, 37%, and 29% for Hek293T, HaCaT, and Caco-2, respectively. To the best of our knowledge, this is the first approach that tackles the combination of CBD with a specific group of terpenes against SARS-CoV-2 in different cell lines. The differential effectiveness of formulations according to the cell line can be relevant to understanding the pattern of virus infectivity and the host inflammation response, and lead to new therapeutic strategies.

The endocannabinoid system (ECS) refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Cannabinoid receptors (CBRs) are highly expressed in the central nervous system and many peripheral tissues. Evidence suggests that CB1Rs are expressed in human and murine skeletal muscle mainly in the cell membrane, but a subpopulation is present also in the mitochondria. However, very little is known about the latter population. To date, the connection between the function of CB1Rs and the regulation of intracellular Ca2+ signaling has not been investigated yet. Tamoxifen-inducible skeletal muscle-specific conditional CB1 knock-down (skmCB1-KD, hereafter referred to as Cre+/−) mice were used in this study for functional and morphological analysis. After confirming CB1R down-regulation on the mRNA and protein level, we performed in vitro muscle force measurements and found that peak twitch, tetanus, and fatigue were decreased significantly in Cre+/− mice. Resting intracellular calcium concentration, voltage dependence of the calcium transients as well as the activity dependent mitochondrial calcium uptake were essentially unaltered by Cnr1 gene manipulation. Nevertheless, we found striking differences in the ultrastructural architecture of the mitochondrial network of muscle tissue from the Cre+/− mice. Our results suggest a role of CB1Rs in maintaining physiological muscle function and morphology. Targeting ECS could be a potential tool in certain diseases, including muscular dystrophies where increased endocannabinoid levels have already been described.

Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a “browning” of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.

White adipose tissue (WAT) possesses the endocannabinoid system (ECS) machinery and produces the two major endocannabinoids (ECs), arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). Accumulating evidence indicates that WAT cannabinoid 1 receptors (CB1R) are involved in the regulation of fat storage, tissue remodeling and secretory functions but their role in controlling lipid mobilization is unclear. In the present study, we used different strategies to acutely increase ECS activity in WAT and tested the consequences on glycerol production as a marker of lipolysis. Treating lean mice or rat WAT explants with JLZ195, which inhibits ECs degrading enzymes, induced an increase in 2-AG tissue contents that was associated with a CB1R-dependent decrease in lipolysis. Direct treatment of rat WAT explants with AEA also inhibited glycerol production while mechanistic studies revealed it could result from the stimulation of Akt-signaling pathway. Interestingly, AEA treatment decreased lipolysis both in visceral and subcutaneous WAT collected on lean subjects suggesting that ECS also reduces fat store mobilization in Human. In obese mice, WAT content and secretion rate of ECs were higher than in control while glycerol production was reduced suggesting that over-produced ECs may inhibit lipolysis activating local CB1R. Strikingly, our data also reveal that acute CB1R blockade with Rimonabant did not modify lipolysis in vitro in obese mice and human explants nor in vivo in obese mice. Taken together, these data provide physiological evidence that activation of ECS in WAT, by limiting fat mobilization, may participate in the progressive tissue remodeling that could finally lead to organ dysfunction. The present findings also indicate that acute CB1R blockade is inefficient in regulating lipolysis in obese WAT and raise the possibility of an alteration of CB1R signaling in conditions of obesity.

White adipose tissue (WAT) possesses the endocannabinoid system (ECS) machinery and produces the two major endocannabinoids (ECs), arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). Accumulating evidence indicates that WAT cannabinoid 1 receptors (CB1R) are involved in the regulation of fat storage, tissue remodeling and secretory functions but their role in controlling lipid mobilization is unclear. In the present study, we used different strategies to acutely increase ECS activity in WAT and tested the consequences on glycerol production as a marker of lipolysis. Treating lean mice or rat WAT explants with JLZ195, which inhibits ECs degrading enzymes, induced an increase in 2-AG tissue contents that was associated with a CB1R-dependent decrease in lipolysis. Direct treatment of rat WAT explants with AEA also inhibited glycerol production while mechanistic studies revealed it could result from the stimulation of Akt-signaling pathway. Interestingly, AEA treatment decreased lipolysis both in visceral and subcutaneous WAT collected on lean subjects suggesting that ECS also reduces fat store mobilization in Human. In obese mice, WAT content and secretion rate of ECs were higher than in control while glycerol production was reduced suggesting that over-produced ECs may inhibit lipolysis activating local CB1R. Strikingly, our data also reveal that acute CB1R blockade with Rimonabant did not modify lipolysis in vitro in obese mice and human explants nor in vivo in obese mice. Taken together, these data provide physiological evidence that activation of ECS in WAT, by limiting fat mobilization, may participate in the progressive tissue remodeling that could finally lead to organ dysfunction. The present findings also indicate that acute CB1R blockade is inefficient in regulating lipolysis in obese WAT and raise the possibility of an alteration of CB1R signaling in conditions of obesity. [ABSTRACT FROM AUTHOR]

Abstract Background The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB1 and CB2), comprising the endocannabinoid system (ECS). In this study, we investigated the ECS based on CB 1 and CB 2 receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB1 and CB2 receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212–2 (WIN-55)] in RCC cell lines. Methods Human RCC cell lines were used for this study. The CB 1 and CB 2 gene expression levels were analyzed using real-time PCR. Flow cytometric, immunocytochemical and western blot analyses were performed to confirm CB1 and CB2 receptor protein expression. The anti-proliferative effects of synthetic cannabinoids were investigated on cell viability assay. The CB1 and CB2 receptors were blocked pharmacologically with the antagonists SR141716A and AM-630, respectively, to investigate the effects of the agonists JWH-133 and WIN-55. Cell cycle, apoptosis and LDH-based cytotoxicity were analyzed on cannabinoid-treated RCC cells. Results The CB1 and CB2 genes expression was shown by real-time PCR and flow cytometric and western blot analysis indicating a higher level of CB2 receptor as compared to CB1 in RCC cells. Immunocytochemical staining also confirmed the expression of the CB1 and CB2 proteins. We also found that the synthetic cannabinoid agonist WIN-55 exerted anti-proliferative and cytotoxic effects by inhibiting the growth of RCC cell lines, while the CB2 agonist JWH-133 did not. Pharmacologically blocking the CB1 and CB2 receptors with their respective antagonists SR141716A and AM-630, followed by the WIN-55 treatment of RCC cells allowed uncovering the involvement of CB2, which led to an arrest in the G0/G1 phase of the cell cycle and apoptosis. Conclusions This study elucidated the involvement of CB2 in the in vitro inhibition of RCC cells, and future applications of CB2 agonists in the prevention and management of RCC are discussed.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors including PPARα, PPARγ, and PPARβ/δ, acting as transcription factors to regulate the expression of a plethora of target genes involved in metabolism, immune reaction, cell differentiation, and a variety of other cellular changes and adaptive responses. PPARs are activated by a large number of both endogenous and exogenous lipid molecules, including phyto- and endo-cannabinoids, as well as endocannabinoid-like compounds. In this view, they can be considered an extension of the endocannabinoid system. Besides being directly activated by cannabinoids, PPARs are also indirectly modulated by receptors and enzymes regulating the activity and metabolism of endocannabinoids, and, vice versa, the expression of these receptors and enzymes may be regulated by PPARs. In this review, we provide an overview of the crosstalk between cannabinoids and PPARs, and the importance of their reciprocal regulation and modulation by common ligands, including those belonging to the extended endocannabinoid system (or “endocannabinoidome”) in the control of major physiological and pathophysiological functions.

There are several findings indicating that the endocannabinoid system (ECS) is an important factor, acting in multiple ways in regulating reproductive function but changes of this system in the bovine endometrium have rarely been investigated; therefore, this study was designed to consider an association between endometrial ECS expression and different stages of the estrous cycles. MRNA expressions of the ECS were investigated during the late luteal phase and estrus using real-time PCR. Following estrous synchronization of sixteen Holstein dairy cows (34±1.3 kg/day of milk production), using two PGF2α injections given 14 days apart, at 30 and 44 days in milk (DIM), blood samples and ultrasonography (US) were performed every other day from the day of second PGF2α injection (44 DIM) until the start of the next estrous cycle (67±2 DIM) to verify CL development and ovulation. Based on blood and US results endometrial tissue was collected on days 16 (late luteal phase) and 21 (estrus) of the synchronized estrous cycle (ovulation = d 0). Real-time PCR analysis of ECS mRNA expression revealed endocannabinoid receptor (CNR2), diacylglycerol lipase (DAGL), cyclooxygenase-2 (COX-2), fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) had significant fold differences when comparing two different stages of the estrous cycle (late luteal phase vs. estrus). CNR2 and DAGL showed 2.01 and 2.57 fold increase, respectively (P=0.04 and P=0.02), in estrous cows. Among the analyzed genes FAAH (P=0.01) and MGLL (P=0.02) were significantly down-regulated in estrous cows, with a 5.01- and 2.44-fold difference in mRNA expression, respectively. Overall, this study highlights an association between the expression of the ECS in the bovine endometrium and stage of the estrous cycle. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the effect of rimonabant, a cannabinoid receptor type 1 antagonist, on calcium/calmodulin- dependent protein kinase II and cannabinoid receptor type 1 in chronic intermittent hypoxia. Materials and methods: Healthy male rats were divided into control group, intermittent hypoxia group for 4 or 6 weeks, hypoxic intervention group that received rimonabant (1 mg/kg/d) before exposure to hypoxia for 4 or 6 weeks (n = 10/group). Morphological changes and expressions of the two indexes in the cerebral hippocampus cells were determined by haematoxylin-eosin staining and immunohistochemistry, respectively. Results: In the intermittent hypoxia group at 4 weeks, the hippocampal cells were damaged with sparse cytoplasm and unclear boundaries, which are even worse at 6 weeks. In contrast, the hippocampal cells of the hypoxic intervention group were neatly arranged at 4 weeks. At 6 weeks, cells were larger with scarce cytoplasm and nuclear changes indicative of cell death. Calcium/calmodulin-dependent protein kinase II and cannabinoid receptor type 1 expression in the cerebral hippocampus was elevated in the intermittent hypoxia group at 4 weeks with even greater at 6 weeks. Cannabinoid receptor type 1 expression was reduced in the hypoxic intervention group compared to the intermittent hypoxia group. Correlation analysis revealed significant positive correlation of them in the intermittent hypoxia group. Conclusions: Chronic intermittent hypoxia induced structural damage in the hippocampus and increased cannabinoid receptor type 1 and calcium/calmodulin-dependent protein kinase II expression, which may mediate cognitive impairment associated with chronic intermittent hypoxia. Rimonabant had a protective effect against chronic intermittent hypoxia. [ABSTRACT FROM AUTHOR]

Background: The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB1 and CB2), comprising the endocannabinoid system (ECS). In this study, we investigated the ECS based on CB 1 and CB 2 receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB1 and CB2 receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212-2 (WIN-55)] in RCC cell lines.Methods: Human RCC cell lines were used for this study. The CB 1 and CB 2 gene expression levels were analyzed using real-time PCR. Flow cytometric, immunocytochemical and western blot analyses were performed to confirm CB1 and CB2 receptor protein expression. The anti-proliferative effects of synthetic cannabinoids were investigated on cell viability assay. The CB1 and CB2 receptors were blocked pharmacologically with the antagonists SR141716A and AM-630, respectively, to investigate the effects of the agonists JWH-133 and WIN-55. Cell cycle, apoptosis and LDH-based cytotoxicity were analyzed on cannabinoid-treated RCC cells.Results: The CB1 and CB2 genes expression was shown by real-time PCR and flow cytometric and western blot analysis indicating a higher level of CB2 receptor as compared to CB1 in RCC cells. Immunocytochemical staining also confirmed the expression of the CB1 and CB2 proteins. We also found that the synthetic cannabinoid agonist WIN-55 exerted anti-proliferative and cytotoxic effects by inhibiting the growth of RCC cell lines, while the CB2 agonist JWH-133 did not. Pharmacologically blocking the CB1 and CB2 receptors with their respective antagonists SR141716A and AM-630, followed by the WIN-55 treatment of RCC cells allowed uncovering the involvement of CB2, which led to an arrest in the G0/G1 phase of the cell cycle and apoptosis.Conclusions: This study elucidated the involvement of CB2 in the in vitro inhibition of RCC cells, and future applications of CB2 agonists in the prevention and management of RCC are discussed. [ABSTRACT FROM AUTHOR]

N-stearoylthrosine (NST), a synthesized anandamide (AEA) analogue, plays a neuroprotective role in neurodegenerative diseases and cerebrovascular diseases. Several studies have demonstrated that the endocannabinoids systems (ECS) are involved in the neuroprotective effects against cerebral ischemic injury. Oxygen-glucose deprivation (OGD)-induced neuronal injury elevated the levels of endocannabinoids and activated ECS. This research was conducted to investigate the neuroprotective effect of NST against OGD-induced neuronal injury in cultured primary cortical neurons and the potential mechanism involved. Cortical neurons were treated with NST at indicate concentrations for 30 min prior to injury and OGD injured neurons were incubated with normal conditions for 0–24 h. The best neuroprotective effect of NST against OGD-induced injury occurred at 10 μM. All data indicated that the neuroprotective effect of NST against OGD-induced injury resulted from blocking anandamide membrane transporter (AMT) (IC 50 = 11.74 nM) and inhibiting fatty acid amide hydrolase activity (FAAH) (IC 50 = 16.54 nM). Our findings demonstrated that NST has an important role in cerebral ischemic injury pathological progression through activating cannabinoid receptors by inhibiting AEA inactivation system. These data suggested a potential role for NST in the therapeutic consideration of cerebral ischemic injury. However, inhibition of AEA inactivation system may provide a neuroprotective effect during cerebral ischemic injury. [ABSTRACT FROM AUTHOR]

Compelling evidence supports the involvement of the endocannabinoid system (ECS) in psychosis vulnerability. We here evaluated the transcriptional regulation of ECS components in human peripheral blood mononuclear cells (PBMCs) obtained from subjects suffering from bipolar disorder, major depressive disorder and schizophrenia, focusing in particular on the effects of DNA methylation. We observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in schizophrenic patients (N=25) with no changes in any other disorder. We confirmed the regulation of CNR1 in a well-validated animal model of schizophrenia, induced by prenatal methylazoxymethanol (MAM) acetate exposure (N=7 per group) where we found, in the prefrontal cortex, a significant increase in CNR1 expression and a consistent reduction in DNA methylation at specific CpG sites of gene promoter. Overall, our findings suggest a selective dysregulation of ECS in psychosis, and highlight the evaluation of CNR1 DNA methylation levels in PBMCs as a potential biomarker for schizophrenia. [ABSTRACT FROM AUTHOR]

Endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)], endogenously produced arachidonate-based lipids, are anti-inflammatory physiological ligands for two known cannabinoid receptors, CB1 and CB2, yet the molecular and cellular mechanisms underlying their effects after brain injury are poorly defined. In the present study, we hypothesize that traumatic brain injury (TBI)-induced loss of endocannabinoids exaggerates neurovascular injury, compromises brain-cerebrospinal fluid (CSF) barriers (BCB) and causes behavioral dysfunction. Preliminary analysis in human CSF and plasma indicates changes in endocannabinoid levels. This encouraged us to investigate the levels of endocannabinoid-metabolizing enzymes in a mouse model of controlled cortical impact (CCI). Reductions in endocannabinoid (2-AG and AEA) levels in plasma were supported by higher expression of their respective metabolizing enzymes, monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and cyclooxygenase 2 (Cox-2) in the post-TBI mouse brain. Following increased metabolism of endocannabinoids post-TBI, we observed increased expression of CB2, non-cannabinoid receptor Transient receptor potential vanilloid-1 (TRPV1), aquaporin 4 (AQP4), ionized calcium binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and acute reduction in cerebral blood flow (CBF). The BCB and pericontusional cortex showed altered endocannabinoid expressions and reduction in ventricular volume. Finally, loss of motor functions and induced anxiety behaviors were observed in these TBI mice. Taken together, our findings suggest endocannabinoids and their metabolizing enzymes play an important role in the brain and BCB integrity and highlight the need for more extensive studies on these mechanisms. • TBI leads to chronic vascular, ventricular, and neurological deficits. • Brain barriers are compromised after traumatic brain injury. • Compromised brain-CSF barrier (BCB) shows altered cannabinoid regulation. • Altered endocannabinoid system (ECS) reduces endocannabinoids (2-AG and AEA). • Restoring cannabinoid homeostasis may promote neurological recovery after TBI. [ABSTRACT FROM AUTHOR]

8-Chloro-1-(2′,4′-dichlorophenyl)- N -piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2- c ]pyrazole-3-carboxamide 9a was discovered as potent and selective CB 1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB 1 cannabinoid receptor (CB 1 R), expressed as K i , of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a , we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a K i value for CB 1 R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i , as well as for 12 . Moreover, the structural features of the synthesized compounds necessary for CB 1 R were investigated. Amongst the novel series, effects on CB 1 R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2- c ]pyrazole scaffold. Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB 1 R antagonist based drug discovery is confirmed. [ABSTRACT FROM AUTHOR]

Highlights: [•] CB1 blockade in the PVN increases fasting-induced hyperphagia. [•] CB1 blockade in the PVN enhances the orexigenic effect of ghrelin. [•] CB1 blockade potentiates ghrelin-induced PVN hypoactivity. [Copyright &y& Elsevier]

Abstract: Objective: The vasorelaxant effect of 2-arachidonoylglycerol (2-AG) has been well characterised in animals. 2-AG is present in human vascular cells and is up-regulated in cardiovascular pathophysiology. However, the acute vascular actions of 2-AG have not been explored in humans. Approach: Mesenteric arteries were obtained from patients receiving colorectal surgery and mounted on a myograph. Arteries were contracted and 2-AG concentration–response curves were carried out. Mechanisms of action were characterised pharmacologically. Post hoc analysis was carried out to assess the effects of cardiovascular disease/risk factors on 2-AG responses. Results: 2-AG caused vasorelaxation of human mesenteric arteries, independent of cannabinoid receptor or transient receptor potential vanilloid-1 activation, the endothelium, nitric oxide or metabolism via monoacyglycerol lipase or fatty acid amide hydrolase. 2-AG-induced vasorelaxation was reduced in the presence of indomethacin and flurbiprofen, suggesting a role for cyclooxygenase metabolism 2-AG. Responses to 2-AG were also reduced in the presence of Cay10441, L-161982 and potentiated in the presence of AH6809, suggesting that metabolism of 2-AG produces both vasorelaxant and vasoconstrictor prostanoids. Finally, 2-AG-induced vasorelaxation was dependent on potassium efflux and the presence of extracellular calcium. Conclusions: We have shown for the first time that 2-AG causes vasorelaxation of human mesenteric arteries. Vasorelaxation is dependent on COX metabolism, activation of prostanoid receptors (EP4 & IP) and ion channel modulation. 2-AG responses are blunted in patients with cardiovascular risk factors. [Copyright &y& Elsevier]

Abstract: High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum as novel nanomolar inhibitor (EC50 =290nM) of cellular uptake of the endocannabinoid anandamide (AEA). Noteworthy, guineensine did not inhibit endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) nor interact with cannabinoid receptors or fatty acid binding protein 5 (FABP5), a major cytoplasmic AEA carrier. Activity-based protein profiling showed no inhibition of serine hydrolases. Guineensine also inhibited the cellular uptake of 2-arachidonoylglycerol (2-AG). Preliminary structure–activity relationships between natural guineensine analogs indicate the importance of the alkyl chain length interconnecting the pharmacophoric isobutylamide and benzodioxol moieties for AEA cellular uptake inhibition. Guineensine dose-dependently induced cannabimimetic effects in BALB/c mice shown by strong catalepsy, hypothermia, reduced locomotion and analgesia. The catalepsy and analgesia were blocked by the CB1 receptor antagonist rimonabant (SR141716A). Guineensine is a novel plant natural product which specifically inhibits endocannabinoid uptake in different cell lines independent of FAAH. Its scaffold may be useful to identify yet unknown targets involved in endocannabinoid transport. [Copyright &y& Elsevier]

Down syndrome (DS) or Trisomy 21 is the most common genetic cause of mental retardation with severe learning and memory deficits. DS is due to the complete or partial triplication of human chromosome 21 (HSA21) triggering gene overexpression and protein synthesis alterations responsible for a plethora of mental and physical phenotypes. Among the diverse brain target systems that affect hippocampal-dependent learning and memory deficit impairments in DS, the upregulation of the endocannabinoid system (ECS), and notably the overexpression of the cannabinoid type-1 receptor (CB1), seems to play a major role. Combining various protein and gene expression targeted approaches using western blot, qRT-PCR and FISH techniques, we investigated the expression pattern of ECS components in the hippocampus (HPC) of male Ts65Dn mice. Among all the molecules that constitute the ECS, we found that the expression of the CB1 is altered in the HPC of Ts65Dn mice. CB1 distribution is differentially segregated between the dorsal and ventral part of the HPC and within the different cell populations that compose the HPC. CB1 expression is upregulated in GABAergic neurons of Ts65Dn mice whereas it is downregulated in glutamatergic neurons. These results highlight a complex regulation of the CB1 encoding gene (Cnr1) in Ts65Dn mice that could open new therapeutic solutions for this syndrome. • Segregation of CB1 distribution between the dorsal and ventral HPC of Ts65Dn mice • Alteration of CB1 mRNA and protein levels in the dHPC of Ts65Dn mice • Increase of CB1 mRNA in GABAergic interneurons of dHPC of Ts65Dn mice • Decrease of CB1 mRNA in pyramidal layers of dHPC of Ts65Dn mice • CB1 as a potential therapeutic target for HPC-related disorders in DS [ABSTRACT FROM AUTHOR]

Highlights: [•] CB1 receptor antagonist blocked extinction process in contextual fear conditioning. [•] TRPV1 channel antagonist favored short-term extinction of aversive memories. [•] ECS activation influenced the extinction process of fear memories. [•] ECS activation contrasted the stress effects on fear memory. [ABSTRACT FROM AUTHOR]

Highlights: [•] IL1β abolishes the sensitivity of CB1 receptors. [•] IL1β-CB1Rs(Glu) interaction is controlled by the PKC/TRPV1 pathway. [•] IL1β-CB1Rs(GABA) interaction is controlled by BDNF/trkB signaling. [ABSTRACT FROM AUTHOR]

Abstract: Cannabinoids, the active components of cannabis (Cannabis sativa) extracts, have attracted the attention of human civilizations for centuries, much earlier than the discovery and characterization of their substrate of action, the endocannabinoid system (ECS). The latter is an ensemble of endogenous lipids, their receptors [in particular type-1 (CB1) and type-2 (CB2) cannabinoid receptors] and metabolic enzymes. Cannabinoid signaling regulates cell proliferation, differentiation and survival, with different outcomes depending on the molecular targets and cellular context involved. Cannabinoid receptors are expressed and functional from the very early developmental stages, when they regulate embryonic and trophoblast stem cell survival and differentiation, and thus may affect the formation of manifold adult specialized tissues derived from the three different germ layers (ectoderm, mesoderm and endoderm). In the ectoderm-derived nervous system, both CB1 and CB2 receptors are present in neural progenitor/stem cells and control their self-renewal, proliferation and differentiation. CB1 and CB2 show opposite patterns of expression, the former increasing and the latter decreasing along neuronal differentiation. Recently, endocannabinoid (eCB) signaling has also been shown to regulate proliferation and differentiation of mesoderm-derived hematopoietic and mesenchymal stem cells, with a key role in determining the formation of several cell types in peripheral tissues, including blood cells, adipocytes, osteoblasts/osteoclasts and epithelial cells. Here, we will review these new findings, which unveil the involvement of eCB signaling in the regulation of progenitor/stem cell fate in the nervous system and in the periphery. The developmental regulation of cannabinoid receptor expression and cellular/subcellular localization, together with their role in progenitor/stem cell biology, may have important implications in human health and disease. [Copyright &y& Elsevier]

Abstract: Objective: The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid (CB) receptor, whose role in the gastrointestinal (GI) tract remains unknown. Here we studied the significance of GPR55 in the regulation of GI motility. Design: GPR55 mRNA and protein expression were measured by RT-PCR and immunohistochemistry. The effects of the GPR55 agonist O-1602 and a selective antagonist cannabidiol (CBD) were studied in vitro and in vivo and compared to a non-selective cannabinoid receptor agonist WIN55,212-2. CB1/2 −/− and GPR55−/− mice were employed to identify the receptors involved. Results: GPR55 was localized on myenteric neurons in mouse and human colon. O-1602 concentration-dependently reduced evoked contractions in muscle strips from the colon (∼60%) and weakly (∼25%) from the ileum. These effects were reversed by CBD, but not by CB1 or CB2 receptor antagonists. I.p. and i.c.v. injections of O-1602 slowed whole gut transit and colonic bead expulsion; these effects were absent in GPR55−/− mice. WIN55,212-2 slowed whole gut transit effects, which were counteracted in the presence of a CB1 antagonist AM251. WIN55,212-2, but not O-1602 delayed gastric emptying and small intestinal transit. Locomotion, as a marker for central sedation, was reduced following WIN55,212-2, but not O-1602 treatment. Conclusion: GPR55 is strongly expressed on myenteric neurons of the colon and it is selectively involved in the regulation of colonic motility. Since activation of GPR55 receptors is not associated with central sedation, the GPR55 receptor may serve as a future target for the treatment of colonic motility disorders. [Copyright &y& Elsevier]

Abstract: The endocannabinoid system (ECS) represents one of the major determinants of metabolic disorders. We investigated potential changes in the endogenous levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) in some peripheral organs and tissues of obese Zucker fa/fa and lean Zucker fa/+ rats by qPCR, liquid chromatography mass spectrometry, western blot and enzymatic activity assays. At 10–12 weeks of age AEA levels were significantly lower in BAT, small intestine and heart and higher in soleus of Zucker fa/fa rats. In this tissue, also the expression of CB1 receptors was higher. By contrast in Zucker fa/fa rats, 2-AG levels were changed (and lower) solely in the small and large intestine. Finally, in Zucker fa/fa , PEA levels were unchanged, whereas OEA was slightly lower in BAT, and higher in the large intestine. Interestingly, these differences were accompanied by differential alterations of the genes regulating ECS tone. In conclusion, the levels of endocannabinoids are altered during obesity in a way partly correlating with changes of the genes related to their metabolism and activity. [Copyright &y& Elsevier]

Abstract: Tobacco dependence is the leading preventable cause of adult morbidity and mortality in the world. Despite the magnitude of this global public health problem, relatively few medications (i.e. nicotine replacement therapy and sustained-release bupropion) are currently approved for the treatment of this pandemic. Nicotine and other components in tobacco smoke are more likely to produce a dependence state in cigarette smokers than alcohol and cocaine in regular users of those drugs of abuse. As our understanding of the neurobiology of tobacco dependence increases, so, too, grows the number of potential therapeutic targets by which we can intervene in this devastating addiction. The purpose of this manuscript is to review three novel mechanisms of action that may serve as therapeutic targets for the pharmacologic treatment of tobacco dependence. For each of these therapeutic targets, we discuss medications in development that affect these pathophysiologic mechanisms. First, we examine the role of the endocannabinoid system (ECS) in the development of nicotine dependence and highlight the development of rimonabant, the first selective antagonist of the cannabinoid type 1 (CB-1) receptor. Second, we explore how heterogeneity among various subtypes of nicotinic receptors might be exploited to develop more specific agents acting at these receptors such as varenicline—a partial agonist at the α4β2 nicotinic receptor. Finally, we examine how selective inhibitors of monoamine oxidase (MAO) such as selegiline might be used as adjunctive medications for the treatment of tobacco dependence. [Copyright &y& Elsevier]

Endocannabinoid system has been extensively studied in recent decades, particularly the cannabinoid receptors CB1 and CB2, due to their important role in neuroinflammation. Among these, CB2 has gained prominence due to its selective overexpression in glial cells during neuroinflammation. In contrast to CB1 agonists, CB2 agonists have no side effects such as ataxia, hypothermia, euphoria, psychological, or addiction liabilities. CB2 and its selective agonists' above-mentioned unique properties have become a research focus in neurodegenerative disorders such as Alzheimer's disease (AD). The review discusses the neuroprotective role of CB receptors, particularly CB2, in AD, as well as the significance and limitations of this research., (© 2021 Wiley Periodicals LLC.)

The endocannabinoid system (ECS) is a complex physiological network involved in creating homeostasis and maintaining human health. Studies of the last 40 years have shown that endocannabinoids (ECs), a group of bioactive lipids, together with their set of receptors, function as one of the most important physiologic systems in human body. ECs and cannabinoid receptors (CBRs) are found throughout the body: in the brain tissues, immune cells, and in the peripheral organs and tissues as well. In recent years, ECs have emerged as key modulators of affect, neurotransmitter release, immune function, and several other physiological functions. This modulatory homoeostatic system operates in the regulation of brain activity and states of physical health and disease. In several research studies and patents the ECS has been recognised with neuro-protective properties thus it might be a target in neurodegenerative diseases. Most immune cells express these bioactive lipids and their receptors, recent data also highlight the immunomodulatory effects of endocannabinoids. Interplay of immune and nervous system has been recognized in past, recent studies suggest that ECS function as a bridge between neuronal and immune system. In several ongoing clinical trial studies, the ECS has also been placed in the anti-cancer drugs spotlight. This review summarizes the literature of cannabinoid ligands and their biosynthesis, cannabinoid receptors and their distribution, and the signaling pathways initiated by the binding of cannabinoid ligands to cannabinoid receptors. Further, this review highlights the functional role of cannabinoids and ECS in blood cell development, neuroimmune interactions and associated disorders. Moreover, we highlight the current state of knowledge of cannabinoid ligands as the mediators of neuroimmune interactions, which can be therapeutically effective for neuro-immune disorders and several diseases associated with neuroinflammation. • Endocannabinoids are known to have therapeutic potential in neuroinflammation and immune disorders. • Cannabinoid receptors are expressed in brain tissue, immune cells and blood cells. • Endocannabinoid system could be an effective target for the treatment of different blood disorders. • Endocannabinoid system regulates neuroimmune axis. [ABSTRACT FROM AUTHOR]