NITRIC-OXIDE SYNTHASE AND NEURONAL VULNERABILITY IN PARKINSONS-DISEASE

Parkinson's disease is characterized by a loss of dopaminergic neurons in the mesencephalon. Although the mechanism of this neuronal loss is still unknown, oxidative stress is very likely involved in the cascad e of events leading to nerve cell death. Since nitric oxide could be i nvolved in the production of free radicals, we analysed, using immunoh istochemistry and histochemistry, the production systems of nitric oxi de in the mesencephalon of four patients with idiopathic Parkinson's d isease and three matched control subjects. Using specific antibodies d irected against the inducible isoform of nitric oxide synthase (the en zyme involved in the synthesis of nitric oxide), we found evidence to suggest that this isoform was present solely in glial cells displaying the morphological characteristics of activated macrophages. Immunohis tochemical analysis performed with antibodies against the neuronal iso form of nitric oxide synthase, however, revealed perikarya and process es of neurons but no glial cell staining. The number of nitric oxide s ynthase-containing cells was investigated by histoenzymology, using th e NADPH-diaphorase activity of nitric oxide synthase. Histochemistry r evealed (i) a significant increase in NADPH-diaphorase-positive glial cell density in the dopaminergic cell groups characterized by neuronal loss in Parkinson's disease ana(ii) a neuronal loss in Parkinson's di sease that was two-fold greater for pigmented NADPH-diaphorase-negativ e neurons than for pigmented NADPH-diaphorase-positive neurons. These data suggest a potentially deleterious role of glial cells producing e xcessive levels of nitric oxide in Parkinson's disease, which may be n eurotoxic for a subpopulation of dopaminergic neurons, especially thos e not expressing NADPH-diaphorase activity. However, it cannot be excl uded that the presence of glial cells expressing nitric oxide synthase in the substantia nigra of patients with Parkinson's disease represen ts a consequence of dopaminergic neuronal loss.