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‐l,2,3,6‐tetrahydropyridine (MPTP) lesions, spontaneous recovery of the damaged DA nigrostriatal system was seen within 12 weeks. A variety of trophic factors and growth factors (GMl ganglioside, GDla ganglioside, acidic fibroblast growth factor, adrenal medullary grafts with and without nerve growth factor source) enhanced this recovery from MPTP insult. In marked contrast, 12‐month‐old male C57BL/6 mice showed greater sensitivity to MPTP, did not demonstrate spontaneous recovery, and showed no recovery in the presence of those same growth factors. Therefore, the DA nigrostriatal system at 12 months of age in these mice, even though apparently anatomically and chemically indistinguishable from their 3‐month‐old counterparts, nonetheless showed a markedly altered ability to recover from MPTP insult, even in the presence of growth factors. It is possible that these DA neurons in 12‐month‐old mice are functionally damaged and unable to recover from insult from reactive oxygen intermediates at a time point prior to frank anatomical and neurochemical deterioration. The implications of such functional deterioration suggest several potential protective strategies to ameliorate such damage.