Targeting CB(2) receptor as a neuroinflammatory modulator in experimental autoimmune encephalomyelitis.
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 cannabinoid 2 receptor (CB(2)R) in the central nervous system (CNS) and detected the level of CB(2)R expression during experimental autoimmune encephalomyelitis (EAE) by RT-PCR, Western blot and immunostaining. Our results show that CB(2)R was expressed in neurons, microglia and astrocytes. During EAE, the expression of CB(2)R in spinal cord rose slowly at days 9 and 17 post immunization (p.i.), and elevated rapidly at day 28 p.i., while the expression of CB(2)R in spleen elevated rapidly and got a plateau at days 17 and 28 p.i. Only the increase of CB(2)R expression in spinal cord demonstrated a significant difference when compared to control mice immunized with complete Freund's adjuvant (CFA). The selective CB(2)R antagonist (SR144528) exacerbated EAE clinical severity accompanied by weight loss. SR144528 inhibited the expression of CB(2)R, but increased the expression of CB(1)R in brain, spinal cord and spleen. The administration of SR144528 declined interferon-γ, IL-17, IL-4, IL-10, IL-1β, IL-6 and tumor necrosis factor-α, but increased CX3CL1 in brain and/or spinal cord. In contrast, IL-17 and MCP-1 were increased, while CX3CL1 was decreased in splenic mononuclear cells as compared to vehicle controls. These results indicate that manipulation of CB(2)R may have therapeutic value in MS, but its complexity remains to be considered and studied for further clinical application.
Institute of Neurology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Zhi-Yin
ZY
Lou
Chan
C
Chen
Qing
Q
He
Chong-Bo
CB
Zhao
Bao-Guo
BG
Xiao
D000818:Animals; D001253:Astrocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology; D013154:Spleen / Q000276:immunology
D016207:Cytokines; D043885:Receptor, Cannabinoid, CB2