Neuroprotective Effect of JZL184 in MPP⁺-Treated SH-SY5Y Cells Through CB₂ Receptors

Growing evidence suggests that the endocannabinoid system plays a role in neuroprotection in Parkinson’s disease. Recently, we have shown the neuroprotective effect of monoacylglycerol lipase (MAGL) inhibition with JZL184 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. However, further investigation is needed to determine the neuroprotective mechanisms of the endocannabinoid system on the nigrostriatal pathway. The aim of this work was to investigate whether the neuroprotective effect of JZL184 in mice could be extended to an in vitro cellular model to further understand the mechanism of action of the drug. The SH-SY5Y cell line was selected based on its dopaminergic-like phenotype and its susceptibility to 1-methyl-4-phenylpyridinium iodide (MPP⁺) toxicity. Furthermore, SH-SY5Y cells express both cannabinoid receptors, CB₁ and CB₂. The present study describes the neuroprotective effect of MAGL inhibition with JZL184 in SH-SY5Y cells treated with MPP⁺. The effect of JZL184 in cell survival was blocked by AM630, a CB₂ receptor antagonist, and it was mimicked with JWH133, a CB₂ receptor agonist. Rimonabant, a CB₁ receptor antagonist, did not affect JZL184-induced cell survival. These results demonstrate that the neuroprotective effect of MAGL inhibition with JZL184 described in animal models of Parkinson’s disease could be extended to in vitro models such as SH-SY5Y cells treated with MPP⁺. This represents a useful tool to study mechanisms of neuroprotection mediated by MAGL inhibition, and we provide evidence for the possible involvement of CB₂ receptors in the improvement of cell survival.