Melatonin attenuates MPP⁺-induced neurodegeneration and glutathione impairment in the nigrostriatal dopaminergic pathway

In this study we selected a rat model of Parkinson's disease (PD) by using intrastriatal infusion of the 1-methyl-4-phenyl-pyridinium ion (MPP⁺) to investigate the neuroprotective action of melatonin and its inhibitory activity on MPP⁺-impaired glutathione (GSH) system in the nigrostriatal system. Results show that MPP⁺ caused not only a severe neuronal injury in the striatum and in the ipsilateral substantia nigra (SN), but it also induced a significant decrease in GSH levels and an increase in the GSSG/GSH ratio 3 days after intrastriatal MPP⁺ infusion. Intraperitoneal co-administration of melatonin (10 mg/kg, five times) significantly attenuated MPP⁺-induced nigrostriatal neurotoxicity and GSH impairment. Depletion of cytosolic GSH by L-buthionine sulfoximine (BSO) did not cause neuronal damage by itself. It, however, when co-administrated with MPP⁺, potentiated the GSH reduction in the striatum, without aggravating nigrostriatal neurodegeneration induced by MPP⁺. Moreover, the MPP⁺-caused neuronal damage was positively correlated with a rising ratio of GSSG/GSH, but not with a drop of GSH. These results suggest that the MPP⁺-triggered oxidative stress may play a more important role than the loss of the antioxidant GSH in determining neuronal injury. Interestingly, the neuronal damage and oxidative stress elicited by co-treatment of BSO with MPP⁺ were effectively reduced by melatonin. Our results hence provide direct evidence showing that melatonin attenuates MPP⁺-induced nigrostriatal dopaminergic injury by its ability to impede the increase of GSSG/GSH ratio; therefore melatonin may have therapeutic implications in PD.