Activation of central cannabinoid type 2 receptors, but not on peripheral immune cells, is required for endocannabinoid-mediated neuroprotection in Parkinson´s disease

Background Neuroinflammation is a key feature of Parkinson´s disease (PD), a neurodegenerative disease for which there is no cure. The cannabinoid receptor type 2 (CB2R) is expressed by cells of the innate and adaptive immune systems. Inhibition of monoacylglycerol lipase increases the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), which is neuroprotective in an experimental model of PD. We hypothesize that the beneficial effect of MAGL inhibition with JZL184 is mediated by the activation of CB2R on specific immune cell populations. Methods Experimental parkinsonism was induced by chronic administration of MPTP and probenecid for 5 weeks in wild-type (WT), CB2R transgenic and knockout (KO) mice. Motor behavior and histological techniques were used to determine the status of the nigrostriatal pathway. Myeloid and lymphoid subpopulations and their TNFα ⁺ production were analyzed by low cytometry in the striatum and ventral midbrain. To distinguish whether a central or peripheral CB2R activation is required for neuroprotection, mice were treated with the CB2R agonists JWH133 and RO304. In addition, WT mice were irradiated and transplanted with CB2R KO hematopoietic stem cells to generate chimeric animals lacking CB2R in the peripheral immune system. Finally, we analyzed the transcriptomic profile of the endocannabinoid system in midbrain microglia and astrocytes from PD patients. Results Parkinsonian mice experimented a specific increase in CD4 ⁺ T cell infiltration in the midbrain. The neuroprotective effect of JZL184 was accompanied by a reduction in CD4 ⁺ T cell infiltration, these effects were abolished in CB2R KO mice. CB2R expression was restricted to myeloid cells and lymphocytes, and increased in microglia under parkinsonian conditions. Administration of JWH133, but not RO304, exerted a neuroprotective and immunomodulatory effect similar to that of JZL184. Using chimeric mice, we demonstrated that central CB2R activation is required for neuroprotection. Transcripts related to 2-AG biosynthesis are downregulated in the midbrain microglia from PD patients. Conclusions Activation of CB2R in the brain prevents nigrostriatal degeneration, CD4 ⁺ T cell infiltration and TNFα production in the midbrain of parkinsonian mice. The reduced 2-AG signaling in microglia from PD patients suggests that activation of microglial CB2R may be an interesting strategy for the treatment of PD.