scholarly journals The CB2 Receptor as a Novel Therapeutic Target for Epilepsy Treatment

2021 ◽  
Vol 22 (16) ◽  
pp. 8961
Author(s):  
Xiaoyu Ji ◽  
Yang Zeng ◽  
Jie Wu
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Seizure Activity ◽  
Epileptiform Activity ◽  
New Drugs ◽  
Future Research ◽  
Receptor Subtype ◽  
Therapeutic Effects ◽  
Cb2 Receptor ◽  
Pilocarpine Model

Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB2 receptors and seizures and emphasize the potential mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia cells. The unique features of CB2Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy.

Modulation and Functional Involvement of CB2 Peripheral Cannabinoid Receptors During B-Cell Differentiation

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3605-3615 ◽  
Author(s):  
Pierre Carayon ◽  
Jean Marchand ◽  
Danielle Dussossoy ◽  
Jean-Marie Derocq ◽  
Omar Jbilo ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Receptor Antagonist ◽  
Cannabinoid Receptors ◽  
Receptor Subtype ◽  
B Cell Differentiation ◽  
Cb2 Receptor ◽  
Cb2 Receptors ◽  
B Cell Subsets

Two subtypes of G-protein–coupled cannabinoid receptors have been identified to date: the CB1 central receptor subtype, which is mainly expressed in the brain, and the CB2 peripheral receptor subtype, which appears particularly abundant in the immune system. We investigated the expression of CB2 receptors in leukocytes using anti-CB2 receptor immunopurified polyclonal antibodies. We showed that peripheral blood and tonsillar B cells were the leukocyte subsets expressing the highest amount of CB2 receptor proteins. Dual-color confocal microscopy performed on tonsillar tissues showed a marked expression of CB2 receptors in mantle zones of secondary follicles, whereas germinal centers (GC) were weakly stained, suggesting a modulation of this receptor during the differentiation stages from virgin B lymphocytes to memory B cells. Indeed, we showed a clear downregulation of CB2 receptor expression during B-cell differentiation both at transcript and protein levels. The lowest expression was observed in GC proliferating centroblasts. Furthermore, we investigated the effect of the cannabinoid agonist CP55,940 on the CD40-mediated proliferation of both virgin and GC B-cell subsets. We found that CP55,940 enhanced the proliferation of both subsets and that this enhancement was blocked by the CB2 receptor antagonist SR 144528 but not by the CB1 receptor antagonist SR 141716. Finally, we observed that CB2 receptors were dramatically upregulated in both B-cell subsets during the first 24 hours of CD40-mediated activation. These data strongly support an involvement of CB2 receptors during B-cell differentiation.

The Cannabinoid Agonist WIN55,212-2 Suppresses Opioid-induced Emesis in Ferrets

2001 ◽  
Vol 94 (5) ◽  
pp. 882-887 ◽  
Author(s):  
Isabelle I. Simoneau ◽  
Maged S. Hamza ◽  
Heriberto P. Mata ◽  
Erin M. Siegel ◽  
Todd W. Vanderah ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Cb1 Receptors ◽  
Cb2 Receptor ◽  
Selective Antagonist ◽  
Receptor Agonists ◽  
Antiemetic Activity ◽  
The Central Nervous System ◽  
Cannabinoid Agonist

Background Cannabinoid receptor agonists reverse nausea and vomiting produced by chemotherapy and radiation therapy in animals and humans but have not been tested against opioid-induced emesis. This study tests the hypothesis that cannabinoid receptor agonists will prevent opioid-induced vomiting. Methods Twelve male ferrets were used. They weighed 1.2-1.6 kg at the beginning and 1.8-2.3 kg at the end of the experiments. All drugs were injected subcutaneously. WIN55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was administered 25 min before morphine. Retches and vomits were counted at 5-min intervals for 30 min after morphine injection. Results Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg/kg, above which the responses decreased. Previous administration of naloxone prevented morphine-induced retching and vomiting. WIN55,212-2 dose-dependently reduced retching and vomiting. The ED50 was 0.05 mg/kg for retches and 0.03 mg/kg for vomits. At 0.13 mg/kg, retching decreased by 76% and vomiting by 92%. AM251, a CB1 receptor-selective antagonist, blocked the antiemetic actions of WIN55,212-2, but AM630, a CB2 receptor-selective antagonist, did not. Conclusions These results demonstrate that WIN55,212-2 prevents opioid-induced vomiting and suggest that the antiemetic activity of WIN55,212-2 occurs at CB1 receptors. This is consistent with findings that CB1 receptors are the predominant cannabinoid receptors in the central nervous system and that antiemetic effects of cannabinoids appear to be centrally mediated.

scholarly journals Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery

2019 ◽  
Vol 11 (15) ◽  
pp. 2019-2037 ◽  
Author(s):  
Francesca Gado ◽  
Serena Meini ◽  
Simone Bertini ◽  
Maria Digiacomo ◽  
Marco Macchia ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Allosteric Modulators ◽  
Cb2 Receptor ◽  
Pharmacological Profile ◽  
Therapeutic Benefits ◽  
Structure Activity ◽  
Biased Signaling ◽  
Orthosteric Ligands

Allosteric modulators of cannabinoid receptors hold great therapeutic potential, as they do not possess intrinsic efficacy, but instead enhance or diminish the receptor's response of orthosteric ligands allowing for the tempering of cannabinoid receptor signaling without the desensitization, tolerance and dependence. Allosteric modulators of cannabinoid receptors have numerous advantages over the orthosteric ligands such as higher receptor type selectivity, probe dependence and biased signaling, so they have a great potential to separate the therapeutic benefits from side effects own of orthosteric ligands. This review aims to give an overview of the CB1 and CB2 receptor allosteric modulators highlighting the structure–activity relationship and pharmacological profile of each classes, and their future promise.

scholarly journals Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ayat Zagzoog ◽  
Asher L. Brandt ◽  
Tallan Black ◽  
Eunhyun D. Kim ◽  
Riley Burkart ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Synthetic Cannabinoid ◽  
Receptor Subtype ◽  
Service Agency ◽  
Subtype Selectivity ◽  
Insight Into

AbstractThe first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

scholarly journals CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Yong Li ◽  
Jimok Kim
Keyword(s):  
Working Memory ◽  
Motor Activity ◽  
Knockout Mice ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Spatial Working Memory ◽  
Fear Memory ◽  
Cb2 Receptor ◽  
Cb2 Receptors

Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.

Modulation and Functional Involvement of CB2 Peripheral Cannabinoid Receptors During B-Cell Differentiation

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3605-3615 ◽  
Author(s):  
Pierre Carayon ◽  
Jean Marchand ◽  
Danielle Dussossoy ◽  
Jean-Marie Derocq ◽  
Omar Jbilo ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Receptor Antagonist ◽  
Cannabinoid Receptors ◽  
Receptor Subtype ◽  
B Cell Differentiation ◽  
Cb2 Receptor ◽  
Cb2 Receptors ◽  
B Cell Subsets

Abstract Two subtypes of G-protein–coupled cannabinoid receptors have been identified to date: the CB1 central receptor subtype, which is mainly expressed in the brain, and the CB2 peripheral receptor subtype, which appears particularly abundant in the immune system. We investigated the expression of CB2 receptors in leukocytes using anti-CB2 receptor immunopurified polyclonal antibodies. We showed that peripheral blood and tonsillar B cells were the leukocyte subsets expressing the highest amount of CB2 receptor proteins. Dual-color confocal microscopy performed on tonsillar tissues showed a marked expression of CB2 receptors in mantle zones of secondary follicles, whereas germinal centers (GC) were weakly stained, suggesting a modulation of this receptor during the differentiation stages from virgin B lymphocytes to memory B cells. Indeed, we showed a clear downregulation of CB2 receptor expression during B-cell differentiation both at transcript and protein levels. The lowest expression was observed in GC proliferating centroblasts. Furthermore, we investigated the effect of the cannabinoid agonist CP55,940 on the CD40-mediated proliferation of both virgin and GC B-cell subsets. We found that CP55,940 enhanced the proliferation of both subsets and that this enhancement was blocked by the CB2 receptor antagonist SR 144528 but not by the CB1 receptor antagonist SR 141716. Finally, we observed that CB2 receptors were dramatically upregulated in both B-cell subsets during the first 24 hours of CD40-mediated activation. These data strongly support an involvement of CB2 receptors during B-cell differentiation.

scholarly journals 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces rapid actin polymerization in HL-60 cells differentiated into macrophage-like cells

2005 ◽  
Vol 386 (3) ◽  
pp. 583-589 ◽  
Author(s):  
Maiko GOKOH ◽  
Seishi KISHIMOTO ◽  
Saori OKA ◽  
Masahiro MORI ◽  
Keizo WAKU ◽  
...  
Keyword(s):  
Actin Filament ◽  
Actin Polymerization ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Morphological Changes ◽  
Biological Activities ◽  
Inflammatory Cells ◽  
Cb2 Receptor ◽  
Physiological Importance ◽  
Filament System

Δ9-Tetrahydrocannabinol, a major psychoactive constituent of marijuana, interacts with specific receptors, i.e. the cannabinoid receptors, thereby eliciting a variety of pharmacological responses. To date, two types of cannabinoid receptors have been identified: the CB1 receptor, which is abundantly expressed in the nervous system, and the CB2 receptor, which is predominantly expressed in the immune system. Previously, we investigated in detail the structure–activity relationship of various cannabinoid receptor ligands and found that 2-AG (2-arachidonoylglycerol) is the most efficacious agonist. We have proposed that 2-AG is the true natural ligand for both the CB1 and CB2 receptors. Despite the potential physiological importance of 2-AG, not much information is available concerning its biological activities towards mammalian tissues and cells. In the present study, we examined the effect of 2-AG on morphology as well as the actin filament system in differentiated HL-60 cells, which express the CB2 receptor. We found that 2-AG induces rapid morphological changes such as the extension of pseudopods. We also found that it provokes a rapid actin polymerization in these cells. Actin polymerization induced by 2-AG was abolished when cells were treated with SR144528, a CB2 receptor antagonist, and pertussis toxin, suggesting that the response was mediated by the CB2 receptor and Gi/o. A phosphoinositide 3-kinase, Rho family small G-proteins and a tyrosine kinase were also suggested to be involved. Reorganization of the actin filament system is known to be indispensable for a variety of cellular events; it is possible that 2-AG plays physiologically essential roles in various inflammatory cells and immune-competent cells by inducing a rapid actin rearrangement.

Molecular Modeling of an Orphan GPR18 Receptor

2019 ◽  
Vol 16 (10) ◽  
pp. 1167-1174 ◽  
Author(s):  
Kamil J. Kuder ◽  
Tadeusz Karcz ◽  
Maria Kaleta ◽  
Katarzyna Kiec-Kononowicz
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Glycine Receptor ◽  
Homology Model ◽  
Orphan Receptor ◽  
Receptor Ligands ◽  
Orphan Receptors ◽  
Inactive Form ◽  
Starting Point ◽  
Endogenous Cannabinoid

Background: : One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Methods: : Main goal of this study, GPR18 inactive form homology model was built on the basis of the evolutionary closest homologous template: Human P2Y1 Receptor crystal structure. Results: : Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion:: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

Yogic Intervention in Sexual Dysfunction - A Review

2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Rakshith K. R. ◽  
Shivakumar . ◽  
Kaushal Sinha ◽  
Vijeth Kumar L. A.
Keyword(s):  
Psychological Functioning ◽  
Empirical Studies ◽  
Empirical Literature ◽  
Future Research ◽  
Therapeutic Effects ◽  
Yoga Therapy ◽  
Cognitive Component ◽  
Beneficial Effects ◽  
Breathing Exercises ◽  
The Mind

Yoga is an ancient practice with Eastern roots that involves both physical postures (Asanas) and breathing techniques (Pranayamas). Yoga therapy for male sexual problems can effectively be treated through Yoga therapy, particularly with the help of Yoga poses and breathing exercises, Yoga has proven itself highly very effective in the treatment of a number of incurable and sometimes terminable diseases. Then again, Yoga's therapeutic effects are just a spin-off and supplementary. Yoga which has proved to be very effective in the treatment of many impossible and incurable diseases, the therapeutic effect of Yoga is only a by product and incidental. Problems related to sex can very well be handled with Yoga as most often these problems are more related to the mind than body. Either they are caused by lack of confidence or stress or fatigue or fear and very few times some physical cause is there. There is also a cognitive component focusing on meditation and concentration, which aids in achieving the goal of union between the self and the spiritual. Although numerous empirical studies have found a beneficial effect of Yoga on different aspects of physical and psychological functioning, claims of Yoga's beneficial effects on sexuality derive from a rich but no empirical literature. The goal of this article is to review the philosophy and forms of Yoga, to review the no empirical and (limited) empirical literatures linking Yoga with enhanced sexuality, and to propose some future research avenues focusing on Yoga as a treatment for sexual disorder.

scholarly journals Cannabinoid receptors distribution in mouse cortical plasma membrane compartments

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hajar Miranzadeh Mahabadi ◽  
Haseeb Bhatti ◽  
Robert B. Laprairie ◽  
Changiz Taghibiglou
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft ◽  
Cannabinoid Receptors ◽  
Gradient Centrifugation ◽  
Brain Regions ◽  
Cb1 Receptor ◽  
The Body ◽  
Cb2 Receptor ◽  
Cortical Tissue ◽  
Ionic Detergent

AbstractThe type 1 and type 2 cannabinoid receptors (CB1 and CB2 receptors) are class A G protein-coupled receptors (GPCRs) that are activated by endogenous lipids called endocannabinoids to modulate neuronal excitability and synaptic transmission in neurons throughout the central nervous system (CNS), and inflammatory processes throughout the body. CB1 receptor is one of the most abundant GPCRs in the CNS and is involved in many physiological and pathophysiological processes, including mood, appetite, and nociception. CB2 receptor is primarily found on immunomodulatory cells of both the CNS and the peripheral immune system. In this study, we isolated lipid raft and non-lipid raft fractions of plasma membrane (PM) from mouse cortical tissue by using cold non-ionic detergent and sucrose gradient centrifugation to study the localization of CB1 receptor and CB2 receptor. Lipid raft and non-lipid raft fractions were confirmed by flotillin-1, caveolin-1 and transferrin receptor as their protein biomarkers. Both CB1 receptor and CB2 receptor were found in non-raft compartments that is inconsistent with previous findings in cultured cell lines. This study demonstrates compartmentalization of both CB1 receptor and CB2 receptor in cortical tissue and warrants further investigation of CB1 receptor and CB2 receptor compartmental distribution in various brain regions and cell types.

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