Neurotoxic and neurotrophic effects of chronic N-methyl-D-aspartate exposure upon mesencephalic dopaminergic neurons in organotypic culture

Current theories regarding the mechanisms of degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease suggest a pivotal role for excitotoxicity. In this study, the effects of chronic exposure of rat ventral mesencephalic slice cultures to the excitotoxin N-methyl-D-aspartate, were investigated. Chronic (18 day) exposure to N-methyl-D-aspartate produced widely varying, dose-dependent effects. High doses (100 mu M) caused a pronounced toxicity upon tyrosine hydroxylase-positive neurons, with the surviving neurons possessing shrunken somata and stunted neurites: co-administration of the N-methyl-D-aspartate receptor antagonist MK-801, inhibited N-methyl-D-aspartate-induced toxicity. In contrast, exposure to a low concentration of N-methyl-D-aspartate (0.1 mu M), stimulated the outgrowth of tyrosine hydroxylase-positive neurites from the culture; this effect was abolished by MK-801. Chronic application of glutamate had similar, though not as pronounced, growth-promoting actions. However, the concentration of glutamate required was 1000 times that of N-methyl-D-aspartate, due to the presence of high-affinity glutamate transport mechanisms. Cultures exposed to a submicromolar concentration of N-methyl-D-aspartate exhibited a significant resistance to subsequent exposure to a lethal (300 mu M) concentration of the toxin. It would thus appear that N-methyl-D-aspartate may have both trophic and toxic actions upon dopaminergic neurons in culture. Moreover, the ability of low doses of N-methyl-D-aspartate to protect neurons in this critical brain region may be of relevance to future attempts to arrest the degeneration associated with Parkinson's disease. The putative mechanisms of these phenomena are discussed.