Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity

Unilateral injection into the right substantia nigra of the catecholaminerg ic neurotoxin 6-hydroxydopamine (6-OHDA) produces extensive loss of dopamin ergic cells ('hemi-parkinsonian rat'). The pineal hormone melatonin, which is a potent antioxidant against different reactive oxygen species and has b een reported to be neuroprotective in vivo and in vitro, was evaluated for potential anti-Parkinson effects in this model. Imbalance in dopaminergic i nnervation between the striata produced by intranigral administration of 6- OHDA results in a postural asymmetry causing rotation away from the nonlesi oned side. Melatonin given systemically prevented apomorphine-induced circl ing behavior in 6-OHDA-lesioned rats. Reduced activity of mitochondrial oxi dative phosphorylation enzymes has been suggested in some neurodegenerative diseases; in particular, selective decrease in complex I activity is obser ved in the substantia nigra of Parkinson's disease patients. Analysis of mi tochondrial oxidative phosphorylation enzyme activities in nigral tissue fr om 6-OHDA-lesioned rats by a novel BN-PAGE histochemical procedure revealed a clear loss of complex I activity, which was protected against in melaton in-treated animals. A good correlation between behavioral parameters and en zymatic (complex I) analysis was observed independent of melatonin administ ration. A deficit in mitochondrial complex I could conceivably contribute t o cell death in parkinsonism via free radical mechanisms, both directly via reactive oxygen species production and by decreased ATP synthesis and ener gy failure. Melatonin may have potential utility in the treatment of neurod egenerative disorders where oxidative stress is a participant.