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

Neuroinflammation is a key feature of Parkinson's disease (PD). The cannabinoid receptor type 2 (CB2R) is expressed by cells of the innate and adaptive immune systems. Inhibition of monoacylglycerol lipase (MAGL) with JZL184 increases the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), which is neuroprotective for dopaminergic neurons. The aim of this study was to determine whether the neuroprotective effect of MAGL inhibition is mediated by CB2R activation on specific immune cell populations. Experimental parkinsonism was induced by chronic administration of MPTP and probenecid. A specific increase in CD4⁺ T cell infiltration was detected in the midbrain of parkinsonian mice and was reduced by administration of JZL184. JZL184 had no effect in CB2R KO mice, suggesting that CB2R is required for neuroprotection. In the brain, CB2R expression was restricted to myeloid cells and lymphocytes, and increased in microglia under parkinsonian conditions. Administration of a central CB2R agonist, JWH133, exerted a beneficial effect similar to that of JZL184, whereas the peripheral agonist RO304 lacked neuroprotective activity. These results were confirmed using chimeric mice. In silico analysis, showed that transcripts related to 2-AG biosynthesis are downregulated in the midbrain microglia from PD patients. Our results show that 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.