Monoacylglycerol lipase inhibition improves motor function and reduces oxidative stress in hemiparkinsonian mice

Parkinson's Disease (PD) is characterized by motor symptoms, loss of dopaminergic neurons, and oxidative stress in the Substantia Nigra pars compacta (SNpc) and striatum of patients, as well as in models of parkinsonism. Recent studies show that the endocannabinoid system present in the basal ganglia has a strong influence on the progression of PD, with the inhibition of the enzyme Monoacylglycerol Lipase (MAGL) being a promising therapeutic strategy. Therefore, the aim of this study was to evaluate the effect of MAGL inhibition on locomotion and oxidative stress in a murine model of hemiparkinsonism. For this study, male C57BL/6J mice were divided into four groups: 1) Control group, 2) 6-OHDA group, which received the hemiparkinsonism model, 3) JZL184 group, which received a dose of 8 mg/kg/day for 7 days of the JZL184 inhibitor, and 4) 6-OHDA + JZL184 group, which had the hemiparkinsonism model and, 14 days later, began administration with JZL184. It was found that the hemiparkinsonism mice showed significant improvements both in locomotor performance and in levels of lipoperoxidation, total antioxidant capacity, superoxide dismutase activity, and in quantity and activity of mitochondrial complex I, once the MAGL inhibitor was administered to this group. Treatment with the JZL184 inhibitor demonstrated improved locomotor ability and reduced oxidative stress levels in the SNpc and striatum of mice with hemiparkinsonism. This suggests that MAGL inhibition could be a therapeutic alternative for PD in the future.