“The effects of cannabinoids are primarily mediated by type-1 cannabinoid receptors in the brain and type-2 cannabinoid receptors (CB2Rs) in the peripheral immune system. However, recent evidence demonstrates that CB2Rs are also expressed in the brain and implicated in neuropsychiatric effects. Diverse types of cells in various regions in the brain express CB2Rs but the cellular loci of CB2Rs that induce specific behavioral effects have not been determined. To manipulate CB2R expression in specific types of cells in the dorsal hippocampus of adult mice, we used Cre-dependent overexpression and CRISPR-Cas9 genome editing techniques in combination with adeno-associated viruses and transgenic mice. Elevation and disruption of CB2R expression in microglia in the CA1 area increased and decreased, respectively, contextual fear memory. In CA1 pyramidal neurons, disruption of CB2R expression enhanced spatial working memory, whereas their overexpression reduced anxiety levels assessed as an increase in the exploration time in the central area of open field. Interneuronal CB2Rs were not involved in the modulation of cognitive or emotional behaviors tested in this study. The targeted manipulation of CB2R expression in pyramidal neurons and microglia suggests that CB2Rs in different types of cells in the mature hippocampus play distinct roles in the regulation of memory and anxiety.” https://www.ncbi.nlm.nih.gov/pubmed/28888955 http://www.sciencedirect.com/science/article/pii/S0306452217306292]]>
Tag Archives: CB2
Cannabinoid Receptor 2 Modulates Neutrophil Recruitment in a Murine Model of Endotoxemia.
“The endocannabinoid system consists of endogenous lipid mediators and cannabinoid receptors (CB) 1 and 2. It has previously been demonstrated that activation of the leukocyte-expressed CB2 has anti-inflammatory effects in vivo. Here, we report its role under baseline conditions and in a model of low-dose endotoxemia by comparing CB2 knockout to littermate control mice. CB2-deficient mice displayed significantly more neutrophils and fewer monocytes in the bone marrow under steady state. In initial validation experiments, administration of 1 mg/kg LPS to male C57BL/6J mice was shown to transiently upregulate systemic proinflammatory mediators (peaked at 2 hours) and mobilise bone marrow neutrophils and monocytes into circulation. In CB2 knockout mice, the level of the metalloproteinase MMP-9 was significantly elevated by 2 hours and we also observed augmented recruitment of neutrophils to the spleen in addition to increased levels of Ccl2, Ccl3, Cxcl10, and Il6. Collectively, our data show that the absence of CB2 receptor increases the levels of innate immune cell populations in the bone marrow under steady state. Furthermore, during an acute systemic inflammatory insult, we observe a highly reproducible and site-specific increase in neutrophil recruitment and proinflammatory chemokine expression in the spleen of CB2 knockout mice.” https://www.ncbi.nlm.nih.gov/pubmed/28852269 “In summary, we found that the lack of this GPCR leads to enhanced retention of neutrophils and increased release of monocytes in the bone marrow under steady state. We highlight a critical role for CB2 in regulating neutrophil infiltration to the spleen during acute systemic inflammation. A potential mechanism for this effect is the increased secretion of MMP-9 and Ccl3/Cxcl10 expression in the spleens of CB2 knockout mice. Taken together, we propose a novel role for CB2 in suppressing neutrophil migration to lymphoid organs under inflammatory conditions which we believe warrants further investigation.” https://www.hindawi.com/journals/mi/2017/4315412/]]>
Neuroprotective activity of cannabinoid receptor-2 against oxidative stress and apoptosis in rat pups having experimentally-induced congenital hypothyroidism.
“In this study, it was aimed to show the cannabinoid receptor-2 (CB2) role, which is a part of neuroprotective endocannabinoidal system, against increasing nitric oxide synthetase (iNOS, eNOS) levels and the apoptotic activity (caspase-3, caspase-9 and DNA in situ fragmentation) within the postnatal critical period in pups of pregnant rats with artificially induced maternal thyroid hormone (TH) deficiency. In conclusion, apoptosis was triggered via oxidative stress in hypothyroid pups. Accordingly, neuroprotective activity of CB2 receptors were motivated spontaneously to resist to CNS lesions during the first 3 weeks of postnatal period.” https://www.ncbi.nlm.nih.gov/pubmed/28799288]]>
Cannabinoid receptor 2-63 RR variant is independently associated with severe necroinflammation in HIV/HCV coinfected patients.
“This is the first study to analyze the impact of the rs35761398 variant of the CNR2 gene leading to the substitution of GLN (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with ARG (R) on the clinical presentation of chronic hepatitis in HIV/HCV coinfected patients.
This study shows interesting interplay between the CB2-RR variant and liver necroinflammation in chronic hepatitis patients with HIV/HCV coinfection, an observation of clinical value that coincides with the interest in the use of the CB2 agonists and antagonists in clinical practice emerging from the literature.”
Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors.
“Inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, produces profound anti-inflammatory and neuroprotective effects and improves synaptic and cognitive functions in animal models of Alzheimer’s disease (AD). However, the molecular mechanisms underlying the beneficial effects produced by inhibition of 2-AG metabolism are still not clear.
The cannabinoid receptor type 2 (CB2R) has been thought to be a therapeutic target for AD. Here, we provide evidence, however, that CB2R does not play a role in ameliorating AD neuropathology produced by inactivation of MAGL in 5XFAD APP transgenic mice, an animal model of AD.
Our results suggest that CB2R is not required in ameliorating neuropathology and preventing cognitive decline by inhibition of 2-AG metabolism in AD model animals.”
“Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor.
We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor.
Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.”