Objectives: 

MPTP-mouse model of Parkinson's disease (PD) constitutes a well-known model for studying the participation of oxidative stress, inflammation, and mitochondrial dysfunction in the pathogenesis of PD. The role of iNOS and nNOS on mitochondrial dysfunction under MPTP administration is, however, unclear. Previous reports showed that melatonin (aMT), an important antioxidant and antiinflammatory, exerts neuroprotective properties in different types of neurodegeneration. Here, the participation of iNOS/nNOS in the mitochondrial impairment of the nigrostriatal pathway and aMT treatment, were assayed in iNOS and nNOS deficient mice.

Materials: 

Mice groups: 1) control; 2) MPTP and 3) MPTP + aMT (MPTP, 15 mg/kg; aMT, 10 mg/kg). Complex I activity; NOS activity; mtDNA; OXPHOS expression; respirometry (Oroboros® oxygraph), and behavioral analysis (SMART software) were measured.

Results: 

Complex I activity decreased sharply whereas iNOS activity increased in SN and ST after MPTP. aMT administration counteracted these effects, recovering the control levels. aMT also prevented the mtDNA depletion induced by MPTP. MTPT caused dramatic changes in mitochondrial O2 consumption and bioenergetics, which were counteracted by aMT. MTPT increased the expression of complexes I and II, probably to maintain the O2 flux. Interestingly, aMT administration keeps this increase but in an higher efficient manner as we could prove in the respirometry assays. These biochemical changes were also evident in the behavioral analysis in which the bradykinesia due to MPTP was significantly restored by aMT.

Conclusions: 

Our results suggest that iNOS induction results in an impairment of the mitochondrial function in the SN and ST of MPTP-treated mice. aMT administration counteracted the inflammatory process, restoring the normal mitochondrial function and phenotype of these mice, suggesting an important neuroprotective role for the neurohormone.

Supported in part by grants nordm; PI08-1664 and RD06/0013/0008 (ISCIII), and CTS-101 (Junta de Andalucía).