DOES NEUROMELANIN CONTRIBUTE TO THE VULNERABILITY OF CATECHOLAMINERGIC NEURONS IN MONKEYS INTOXICATED WITH MPTP

The question has been raised as to whether neuromelanin, a by-product of catecholamine metabolism which accumulates during aging in primate midbrain neurons, contributes to the selective vulnerability of subgro ups of dopaminergic neurons in Parkinson's disease. 1-Methyl-4-phenylp yridinium (MPP+) a metabolite of 1-methyl, 4-phenyl, 1,2,3,6-tetrahydr opyridine (MPTP) is toxic to dopaminergic neurons, particularly in pri mates, producing a motor syndrome similar to that observed in Parkinso n's disease. To test whether this neurotoxin preferentially affects me lanized neurons, the survival of melanized and non-melanized catechola minergic neurons was analysed after MPTP intoxication in the midbrain of the cynomolgus monkey (Macaca fascicularis). Experiments were perfo rmed on six animals chronically treated with MPTP (two were severely d isabled, four moderately affected) and two age-matched control monkeys . Two populations of neurons were examined on regularly spaced section s throughout the midbrain: catecholaminergic neurons, identified by ty rosine hydroxylase immunohistochemistry and neuromelanin-containing ne urons, visualized by Masson's method. The total number of neurons of e ach type was estimated in the different midbrain catecholaminergic cel l groups using computer assisted image analysis. In the midbrains of c ontrol animals not all catecholaminergic neurons contained neuromelani n. The percentage of melanized neurons compared to the total populatio n of tyrosine hydroxylase-positive neurons was high in the substantia nigra pars compacta (81.5%) and in the locus coeruleus (98%), intermed iate in the substantia nigra pars lateralis (70%), in the catecholamin ergic cell group A8 (50%), and in the ventral tegmental area (41.5%) a nd almost nil in the central gray substance. In MPTP-treated monkeys, the severity of the loss of catecholaminergic neurons was variable wit hin the different midbrain cell groups, though of similar intensity in severely and mildly disabled monkeys. A relationship was found betwee n the loss of dopaminergic neurons in the different mesencephalic cell groups of MPTP-intoxicated animals and the percentage of melanized ne urons they normally contain (r = 0.98; P = 0.04). The percentage loss of catecholaminergic neurons in the locus coeruleus, the only noradren ergic cell group studied, was lower than expected from the correlation curve obtained for dopaminergic cell groups. Altogether, these findin gs indicate: (i) that dopaminergic neurons are more vulnerable to MPTP -toxicity than noradrenergic neurons; and (ii) that among dopaminergic neurons, those containing neuromelanin are more susceptible, indicati ng a possible role of neuromelanin in MPTP-toxicity. Nevertheless, neu romelanin may only represent one of the factors involved in the neurot oxin-induced neuronal death, since some nigral melanized neurons also survive MPTP-intoxication.