DECREASED TYROSINE-HYDROXYLASE CONTENT IN THE DOPAMINERGIC-NEURONS OFMPTP-INTOXICATED MONKEYS - EFFECT OF LEVODOPA AND GM1 GANGLIOSIDE THERAPY

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein fo und in the remaining cells. The reduced expression of tyrosine hydroxy lase may be due to either the evolving neurodegenerative process or it s downregulation, possibly secondary to chronic levodopa treatment. Th e cellular content of tyrosine hydroxylase was determined in the mesen cephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonia n by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrah ydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatmen t) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalo n of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, th e cellular content of tyrosine hydroxylase was reduced by 40% in the s urviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosi ne hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expressio n of tyrosine hydroxylase found in nigral dopaminergic neurons after p artial degeneration of the mesostriatal dopaminergic system is not inf luenced by levodopa treatment and is partially reversed by GM1 ganglio side administration.