Toxicity of Structural Analogs of 1-methyl-4-Phenyl Pyridinium (MPP+) and Related Compounds on Dopaminergic Neurons in Culture
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MPTP selectively destroys the nigrostriatal dopaminergic neurons in primates and the mouse and produces a neuropathological lesion in the primate similar to that seen in idiopathic Parkinson’s disease (Heikkila, 1984: Langston, 1985; Langston et al., 1983). These findings led to the speculation that environmental toxins may cause idopathic Parkinson’s disease. According to this hypothesis, exposure to a neurotoxin during a short period of time may reduce the number of dopaminergic neurons, so that an age-related slow degeneration of these cells will reduce, at an earlier time, the number of surviving cells to a level insufficient to support normal function. Alternatively, it is possible that long-term exposure to small quantities of a neurotoxin might produce similar effects as short-term exposure to high levels and gradually result in the appearance of clinical symptoms. At present, no chemical has been identified which could be responsible for causing idiopathic Parkinson’s disease. However, in the modern industrial society, humans are exposed to a vast number of xenobiotics, which are novel chemical structures and to which no defense mechanism has developed during evolution. The discovery of MPTP illustrates that a simple chemical which was used as intermediate in chemical syntheses can turn out to be a major neurotoxin. It is therefore important to study xenobiotics on a large scale for their potential neurotoxicity. We have developed culture systems to study the mechanism of action by which MPTP destroys dopaminergic neurons and to search for neurotoxins which, similar to MPTP, produce toxic effects on dopaminergic neurons. Culture systems offer the advantage that relatively large number of compounds can be tested and that their effects can be assessed in absence of interference by the blood brain barrier or metabolizing enzymes.
KeywordsTyrosine Hydroxylase Dopaminergic Neuron Dopaminergic Cell Glyoxylic Acid Dopamine Uptake
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