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The endocannabinoid system has attracted attention as a pharmacological target for several pathological conditions. Cannabinoid (CB2)-selective agonists have been the focus of pharmacological studies because modulation of the CB2 receptor (CB2R) can be useful in the treatment of pain, inflammation, arthritis, addiction, and cancer among other possible therapeutic applications while circumventing CNS-related adverse effects. Increasing number of evidences from different independent preclinical studies have suggested new perspectives on the involvement of CB2R signaling in inflammation, infection and immunity, thus play important role in cancer, cardiovascular, renal, hepatic and metabolic diseases. JWH133 is a synthetic agonist with high CB2R selectivity and showed to exert CB2R mediated antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, and immunomodulatory activities. Cumulative evidences suggest that JWH133 protects against hepatic injury, renal injury, cardiotoxicity, fibrosis, rheumatoid arthritis, and cancer as well as against oxidative damage and inflammation, inhibits fibrosis and apoptosis, and acts as an immunosuppressant. This review provides a comprehensive overview of the polypharmacological properties and therapeutic potential of JWH133. This review also presents molecular mechanism and signaling pathways of JWH133 under various pathological conditions except neurological diseases. Based on the available data, this review proposes the possibilities of developing JWH133 as a promising therapeutic agent; however, further safety and toxicity studies in preclinical studies and clinical trials in humans are warranted.

The biological effects of cannabinoids are mainly mediated by two members of the G-protein-coupled-receptor family: cannabinoid type 1 receptor (CB1R) and cannabinoid type 2 receptor (CB2R). Unlike CB1R, CB2R is considered a “peripheral” cannabinoid receptor. However, recent studies have found that CB2R is widely expressed in the central nervous system and is involved in dopamine related behavioral regulation, including dietary behavior, weight regulation, anxiety, and schizophrenia like behavior. Our previous laboratory research demonstrated that activating CB2R on dopaminergic neurons in the ventral tegmental area can regulate addictive behavior in animals by inhibiting neuronal excitability. However, it is currently unclear whether CB2R on dopaminergic neurons in the substantia nigra compacta (SNc) has similar therapeutic potential. Brain patch clamp results have shown that the CB2R agonist JWH133 significantly inhibits the discharge of SNc dopamine neurons in a concentration dependent manner. The pharmacological blocker AM630 of CB2R can reverse this inhibitory effect, indicating that the expression of CB2R in SNc dopaminergic neurons is functional. After treatment with JWH133, the number of induced action potentials decreased, and the peak potential interval time, action potential start time, and potential amplitude after hyperpolarization amplitude all increased. In addition, synaptic current results showed that JWH133 can significantly reduce the frequency of miniature excitatory postsynaptic currents, indicating that activating CB2R to some extent inhibits the release of presynaptic glutamate and indirectly excites postsynaptic neurons.

Activation of cannabinoid (CB)1 receptors results in attenuation of experimental colitis. Our aim was to examine the role of CB2 receptors in experimental colitis using agonists (JWH133, AM1241) and an antagonist (AM630) in trinitrobenzene sulfonic acid (TNBS)-induced colitis in wildtype and CB2 receptor-deficient (CBSymbol mice.SymbolNo Caption available.MethodsMice were treated with TNBS to induce colitis and then given intraperitoneal injections of the CB2 receptor agonists JWH133, AM1241, or the CB2 receptor antagonist AM630. Additionally, CBSymbol mice were treated with TNBS and injected with JWH133 or AM1241. Animals were examined 3 days after the induction of colitis. The colons were removed for macroscopic and microscopic evaluation, as well as the determination of myeloperoxidase activity. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for CB2 receptor was also performed in animals with TNBS and dextran sodium sulfate colitis.SymbolNo Caption available.ResultsIntracolonic installation of TNBS caused severe colitis. CB2 mRNA expression was significantly increased during the course of experimental colitis. Three-day treatment with JWH133 or AM1241 significantly reduced colitis; AM630 exacerbated colitis. The effect of JWH133 was abolished when animals were pretreated with AM630. Neither JWH133 nor AM1241 had effects in CBSymbol mice.SymbolNo Caption available.ConclusionsWe show that activation of the CB2 receptor protects against experimental colitis in mice. Increased expression of CB2 receptor mRNA and aggravation of colitis by AM630 suggests a role for this receptor in normally limiting the development of colitis. These results support the idea that the CB2 receptor may be a possible novel therapeutic target in inflammatory bowel disease.

Background Growing evidence indicates that cannabinoid type 2 (CB2) receptor activation inhibits neuroinflammation in the pathogenesis of Parkinson’s disease (PD). Nonetheless, the precise mechanisms of CB2 receptor-mediated neuroprotection have not been fully elucidated. The differentiation of microglia from the M1 to M2 phenotype plays a vital role in neuroinflammation. Methods In the present study, we investigated the effect of CB2 receptor activation on the M1/M2 phenotypic transformation of microglia treated with 1-methyl-4-phenylpyridinium (MPP+). The M1 phenotype microglia markers, including inducible nitric oxide (iNOS), interleukin 6 (IL-6), and CD86, and the M2 phenotype microglia markers, including arginase-1 (Arg-1), IL-10, and CD206, were detected by western blots and flow cytometry. The levels of phosphoinositide-3-kinase (PI3K)/Akt and nuclear factor erythroid 2-related factor 2 (Nrf2) were determined by Western blots. Subsequent addition of Nrf2 inhibitors initially revealed the specific mechanism by which CB2 receptors affect phenotypic changes in microglia. Results Our results showed that pretreatment with JWH133 significantly inhibited the MPP + -induced up-regulation of M1 phenotype microglia markers. Meanwhile, JWH133 increased the levels of M2 phenotype microglia markers. JWH133-mediated effects were blocked by co-treatment with AM630. Mechanism studies found that MPP + treatment downregulated PI3K, Akt phosphorylated proteins, and nuclear Nrf2 protein. JWH133 pretreatment promoted PI3K/Akt activation and facilitated nuclear translocation of Nrf2, which was reversed by the PI3K inhibitor. Further studies showed that Nrf2 inhibitors inverted the effect of JWH133 on microglia polarization. Conclusion The results indicate that CB2 receptor activation promotes MPP + -induced microglia transformation from M1 to M2 phenotype through PI3K/Akt/Nrf2 signaling pathway.

Background The combination of the endocannabinoid system (ECS) and the type 2 cannabinoid receptor (CB2R) can activate various signal pathways, leading to distinct pathophysiological roles. This interaction has gained significant attention in recent research on fibrosis diseases. Focal adhesion kinase (FAK) plays a crucial role in regulating signals from growth factor receptors and Integrins. It is also involved in the transformation of fibroblasts into myofibroblasts. This study aims to investigate the impact of the CB2R agonist JWH133 on lung fibrosis and its potential to alleviate pulmonary fibrosis in mice through the FAK pathway. Methods The C57 mice were categorized into five groups: control, BLM, BLM + JWH133, BLM + JWH133 + NC, and BLM + JWH133 + FAK groups.JWH133 was administered to mice individually or in conjunction with the FAK vector. After 21 days, pathological changes in mouse lung tissues, inflammatory factor levels, hydroxyproline levels, and collagen contents were evaluated. Moreover, the levels of the FAK/ERK/S100A4 pathway-related proteins were measured. Results JWH133 treatment decreased inflammatory factor levels, attenuated pathological changes, and reduced extracellular matrix accumulation in the mouse model of bleomycin-induced pulmonary fibrosis; however, these effects were reversed by FAK. JWH133 attenuated fibrosis by regulating the FAK/ERK/S100A4 pathway. Conclusions The results presented in this study show that JWH133 exerts a protective effect against pulmonary fibrosis by inhibiting the FAK/ERK/S100A4 pathway.Therefore, JWH133 holds promise as a potential therapeutic target for pulmonary fibrosis.

Background Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive. One of the receptors, CB receptor 1 (CB 1 ), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB 2 ) is expressed primarily by immune cells. Theoretically, selective CB 2 agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB 2 agonist on arthritis. Methods The expression of CB 2 was analyzed with immunohistochemistry and Western blotting. Interleukin (IL)-6, matrix metalloproteinase-3 (MMP-3), and chemokine (C-C motif) ligand 2 (CCL2) were quantified with enzyme-linked immunosorbent assays (ELISA). Osteoclastogenesis was assessed with tartrate-resistant acid phosphatase staining and the resorption of coated-calcium phosphate. Effect of JWH133, a selective CB 2 agonist, on murine collagen type II (CII)-induced arthritis (CIA) was evaluated with arthritis score, and histological and radiographic changes. IFN-γ and IL-17 production by CII-stimulated splenocytes and serum anti-CII Ab were analyzed by ELISA. Results Immunohistochemistry showed that CB 2 was expressed more in the synovial tissues from the rheumatoid joints than in those from the osteoarthritis joints. CB 2 expression on RA FLS was confirmed with Western blot analysis. JWH133 inhibited IL-6, MMP-3, and CCL2 production from tumor necrosis factor-α-stimulated fibroblast-like synoviocytes (FLS) derived from the rheumatoid joints, and osteoclastogenesis of peripheral blood monocytes. Administration of JWH133 to CIA mice reduced the arthritis score, inflammatory cell infiltration, bone destruction, and anti-CII IgG1 production. Conclusion The present study suggests that a selective CB 2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.

Blood-brain barrier (BBB) disruption and consequent edema formation are the most common brain injuries following intracerebral hemorrhage (ICH). Endocannabinoid receptors can alter the permeability of various epithelial barriers and have potential neuroprotective effects. The present study aimed to explore whether the selective cannabinoid receptor 2 (CNR2) agonist, JWH133, can ameliorate BBB integrity and behavioral outcome by activating Ras-related C3 botulinum toxin substrate 1 (Rac1) following ICH. Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. Animals were randomly divided into the following groups: Sham-operated, ICH+vehicle, ICH+JWH133, ICH+JWH13+vehicle, ICH+JWH133+AM630 (a selective CNR2 antagonist), ICH+AM630, ICH+JWH133 +NSC23766 (a Rac1 antagonist) and ICH+NSC23766. JWH133 and AM630 were independently intraperitoneally administrated at 1 h prior to ICH. NSC23766 was intracerebroventricularly (ICV) administered 30 min prior to ICH. A modified Garcia test, corner test, Evans blue extravasation and brain water content analysis were performed at 24 and 72 h following ICH. Western blotting and pull-down assays were performed at 24 h following ICH. The results demonstrated that JWH133 treatment improved neurofunctional deficits, reduced perihematomal brain edema and alleviated BBB damage at 24 and 72 h following ICH. In addition, JWH133 treatment increased the protein expression levels of guanosine-5′-triphosphate-Rac1 and of the adherens junction proteins occludin, zonula occludens-1 and claudin-5. However, these effects were reversed by AM630 and NSC23766 treatment. In conclusion, the present findings revealed that JWH133 treatment attenuated brain injury in a rat model of ICH via activation of the Rac1 signaling pathway, thus preserving BBB integrity.

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.

Several studies have shown that the G-protein coupled cannabinoid receptor CB2 and its interaction partner p62 are molecularly involved in bone remodeling processes. Pharmacological activation of the CB2 receptor enhanced bone volume in postmenopausal osteoporosis and arthritis models in rodents, whereas knockout or mutation of the p62 protein in aged mice led to Paget’s disease of bone-like conditions. Studies of pharmacological CB2 agonist effects on bone metabolism in p62 KO mice have not been performed to date. Here, we assessed the effect of the CB2-specific agonist JWH133 after a short-term (5 days in 3-month-old mice) or long-term (4 weeks in 6-month-old mice) treatment on structural, dynamic, and cellular bone morphometry obtained by μCT of the femur and histomorphometry of the vertebral bodies in p62 KO mice and their WT littermates in vivo . A genotype-independent stimulatory effect of CB2 on bone formation, trabecular number, and trabecular thickness after short-term treatment and on tissue mineral density after long-term treatment was detected, indicating a weak osteoanabolic function of this CB2 agonist. Moreover, after short-term systemic CB2 receptor activation, we found significant differences at the cellular level in the number of osteoblasts and osteoclasts only in p62 KO mice, together with a weak increase in trabecular number and a decrease in trabecular separation. Long-term treatment showed an opposite JWH133 effect on osteoclasts in WT versus p62 KO animals and decreased cortical thickness only in treated p62 KO mice. Our results provide new insights into CB2 receptor signaling in vivo and suggest that CB2 agonist activity may be regulated by the presence of its macromolecular binding partner p62.

Rationale Male CB1KO mice exhibit stronger aggressive responses than wild-type mice. Objective This study was designed to examine the role of cannabinoid CB2r in social and aggressive behavior. Methods The social interaction test and resident–intruder paradigm were performed in mice lacking CB2r (CB2KO) and in wild-type (WT) littermates. The effects of the CB2r selective agonist JWH133 (1 and 2 mg/kg) on aggression were also evaluated in Oncins France 1 (OF1) mice. Gene expression analyses of monoamine oxidase-A (MAO-A), catechol-o-methyltransferase (COMT), 5-hydroxytryptamine transporter (5-HTT), and 5-HT 1B receptor (5HT 1B r) in the dorsal raphe nuclei (DR) and the amygdala (AMY) were carried out using real-time PCR. Results Group-housed CB2KO mice exhibited higher levels of aggression in the social interaction test and displayed more aggression than resident WT mice. Isolation increased aggressive behavior in WT mice but did not affect CB2KO animals; however, the latter mice exhibited higher levels of social interaction with their WT counterparts. MAO-A and 5-HTT gene expression was significantly higher in grouped CB2KO mice. The expression of 5HT 1B r, COMT, and MAO-A in the AMY was more pronounced in CB2KO mice than in WT counterparts. Acute administration of the CB2 agonist JWH133 significantly reduced the level of aggression in aggressive isolated OF1 mice, an effect that decreased after pretreatment with the CB2 receptor antagonist AM630. Conclusion Our results suggest that CB2r is implicated in social interaction and aggressive behavior and deserves further consideration as a potential new target for the management of aggression.