Targeting CB2 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 (CB2R) in the central nervous system (CNS) and detected the level of CB2R expression during experimental autoimmune encephalomyelitis (EAE) by RT-PCR, Western blot and immunostaining. Our results show that CB2R was expressed in neurons, microglia and astrocytes. During EAE, the expression of CB2R 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 CB2R in spleen elevated rapidly and got a plateau at days 17 and 28 p.i. Only the increase of CB2R expression in spinal cord demonstrated a significant difference when compared to control mice immunized with complete Freund's adjuvant (CFA). The selective CB2R antagonist (SR144528) exacerbated EAE clinical severity accompanied by weight loss. SR144528 inhibited the expression of CB2R, but increased the expression of CB1R 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 CB2R may have therapeutic value in MS, but its complexity remains to be considered and studied for further clinical application.

► There is negative correlation of CB2R expression in CNS and periphery during EAE.
► SR2 suppressed CB2R while up-regulated CB1R in the time-dependent manner.
► SR2 deteriorated EAE, increased IL-17, MCP-1 and CX3CL1 in CNS and in periphery.