Age-related decline in the dopaminergic nigrostriatal system: the oxidative hypothesis and protective strategies

The anatomical and metabolic deterioration of the dopaminergic (DA) nigrostriatal system with age has been hypothesized to occur due to autodestruction by reactive oxygen intermediates derived from oxidative metabolites of DA. We hypothesized that treatment with a presynaptic agonist to diminish DA turnover should confer a protective effect. Pergolide mesylate, a potent D2 agonist with predominantly presynaptic action, when given in the diet (0.5 mg/kg/day) to male Fischer 344 rats from 3 months of age to 26 months of age, preserved the integrity of both cell bodies and terminals of the nigrostriatal system, partially reversed the age-related decline in DA uptake, and had no adverse effects on behavior or postsynaptic DA receptors on striatal neurons compared with age-matched, pair-fed control rats. As a counterpart to this strategy, L-dopa administration (50 mg/kg) to adult male Fischer 344 rats with unilateral nigrostriatal lesions using 6-hydroxy-dopamine, and subsequent fetal mesencephalic grafts resulted in stunted size and neurite outgrowth, diminished tyrosine hydroxylase (TH) expression, diminished behavioral recovery, and diminished ability to reverse lesion-induced D2 receptor changes, compared with saline-treated rats with the same lesion and subsequent graft. This toxic effect, although not seen in intact nigrostriatal systems, may indicate L-dopa toxicity on transplanted DA cells, or on DA cells maximally activated to recover from insult. In 3-month-old male C57BL/6 mice with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions, spontaneous recovery of the damaged DA nigrostriatal system was seen within 12 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)