Immunoregulation of experimental autoimmune encephalomyelitis by the selective CB1 receptor antagonist

Abstract

During immune-mediated demyelinating lesions, the endocannabinoid system is involved in the pathogenesis of both neuroinflammation and neurodegeneration through different mechanisms. Here we explored the cellular distribution of the CB1 receptor (CB1R) in the central nervous system (CNS) and detected the level of CB1R expression during experimental autoimmune encephalomyelitis (EAE) by RT-qPCR, Western blotting, and immunostaining. Expression of CB1R was observed in neurons and microglia/macrophages but was barely detected in astrocytes. During EAE, the expression of CB1R in spinal cords was reduced at days 9, 17, and 28 postimmunization (p.i.), but the level of CB1R expression in spleens did not show a significant difference compared with complete Freund's adjuvant (CFA)-immunized mice. A selective CB1R antagonist (SR141716A) increased EAE clinical score, accompanied by weight loss. Unexpectedly, SR141716A inhibited the expression of CB1R but increased the expression of CB2R in brains, spinal cords, and spleens simultaneously. The administration of SR141716A increased interferon-γ, interleukin-17 (IL-17), and inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-α in brains and/or spinal cords. A similar increase was observed in spontaneous and specific antigen-stimulated splenic mononuclear cells compared with vehicle controls. Interestingly, the expression of CX3CL1 was increased in brains and spinal cords but declined in spleens of EAE mice treated with SR141716A. These results indicate that manipulation of the CB1R may have therapeutic value in MS, but its complexity remains to be carefully considered and studied in further clinical application.

Cannabinoid Modulation of Neuroinflammatory Disorders

“…Interestingly, the selective CB 1 antagonist SR141716A increased EAE clinical score probably by releasing pro-inflammatory cytokines such as IFN-γ, IL-17, IL-6, IL-1β and TNF-α in mice brain and spinal cord. However, such treatment was able to simultaneously increase CB 2 receptors expression in brain, spinal cord and spleen of mice [111]. It is worthy of mention that combined cannabinoid medicine constituted by the two plant-derived cannabinoids THC and CBD have been formulated under an oromucosal mouth spray (Sativex®) to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms associated with MS [112].…”

Neuroprotective Effect Is Driven Through the Upregulation of CB1 Receptor in Experimental Autoimmune Encephalomyelitis

“…Our previous results demonstrated that administration of SR1 deteriorated EAE pathogenesis, accompanied by a shift of Th2 to Th1/Th1 and inflammatory response (Lou et al 2012). Here, local overexpression of Mock-ov-CB1R inhibited the levels of inflammatory factors IL-1β, IL-6, and TNF-α in the spinal cord and shifted Th17 to Th2 subset, further suggesting that CB1R-mediated neuroprotective effect should be associated with the inhibition of the local inflammatory microenvironment.…”

“…Consistently, our previous study demonstrated that a selective CB1R antagonist (SR141716A) increased EAE clinical score, accompanied by weight loss (Lou et al 2012), further suggesting that CB1R participates in immunomodulation in EAE. Here, we constructed lentiviral vector to upregulate CB1R in the lumbar spinal cord 5-6 region and observe the role of CNS CB1R on the occurrence and development of EAE.…”

Brain structural and clinical changes after first episode psychosis: Focus on cannabinoid receptor 1 polymorphisms

“…Furthermore, neuroanatomical studies have found a selective increase of CB1 receptors in schizophrenia patients, especially in the pons (Wong et al, 2010), nucleus accumbens (Ceccarini et al, 2010) and prefrontal cortex, independent of cannabis use (Dean et al, 2001). Under inflammatory conditions, CNR1 mRNA was shown to be over-expressed in multiple regions of the brain (Lou et al, 2012). This effect may be related to the inflammatory theory of schizophrenia, which proposes that inflammation of the brain during prenatal, neonatal and pubertal periods may be involved in the subsequent development of psychosis-related disorders (Busse et al, 2012;Zavitsanou et al, 2013).…”