Manganese (Mn) intoxication, a syndrome known as manganism, is most often associated with prolonged occupational exposure, although individuals with cirrhosis of the liver and related hepatic dysfunction display many of the behavioral and neurological symptoms associated with this disorder. The most prominent symptom from overexposure comprises an irreversible extrapyramidal dysfunction resembling that of Parkinson's disease. Manganism, however, is associated with the preferential degeneration of GABAminergic neurons within the globus pallidus and not the dopaminergic neurons in the substantia nigra. Although the neurotoxic mechanisms provoking increased susceptibility of pallidal neurons to the toxic actions of Mn is not fully understood, there is increasing evidence that the excitatory neurotransmitter, glutamate, as playing a role in the degenerative actions of Mn since neurons within the globus pallidus normally receive glutaminergic input from cells within the subthalamic nuclei. This is supported by studies demonstrating that blocking of the glutamate receptors with the NMDA receptor antagonist, MK-801, prevents lesions produced by intrastriatal injections of Mn. This raises the issue that the selective neurotoxic actions of Mn on pallidal neurons may not be caused by any one factor but are likely an amalgamation of several processes occurring simultaneously which include 1) accumulation of Mn in the globus pallidus, 2) similarity between the cytotoxic actions of glutamate and Mn involving mitochondrial dysfunction leading to oxidative stress, 3) Mn inhibition of astrocytic glutamate transport and metabolism leading to increase synaptic levels of glutamate and 4) increased uptake of Mn in pallidal neurons by activated glutamate channels. Thus, it is reasonable to hypothesize that treatment of Mn overdoses with a drug which inhibits both glutamate release and oxidative stress may prove useful in the initial stages of manganism. Interestingly, there is a drug on the market, riluzole, currently approved for treatment of amyotrophic lateral sclerosis (ALS), which mechanistically behaves in this fashion. Riluzole functions by inhibiting glutamate release as well as its actions as both an antioxidant and an antagonist of the ionotropic glutamate receptor. Thus, the combined pharmacological actions of riluzole as both an antioxidant and inhibitor of glutamate activity may make it an ideal drug for the treatment of manganism. As will be described in more detail in this proposal, our preliminary studies, in fact, support this hypothesis. Accordingly, the studies proposed in this grant are designed to 1) examine the mechanism by which glutamate facilitates Mn toxicity, 2) characterize the biochemical mechanisms responsible for the neuroprotective actions of riluzole and 3) demonstrate the neuroprotective actions of riluzole in Mn exposed mice.
Overexposure to high atmospheric levels of manganese can lead to a syndrome characterized by an irreversible extrapyramidal dysfunction resembling that of Parkinson's disease. Although it is known that manganism is associated with the preferential degeneration of GABAminergic neurons, the mechanism for this selective toxicity is not fully understood. Thus, the studies proposed in this grant is relevant to human health in that it will investigate new mechanisms to explain the selective toxic actions of manganese in human brain and provide the necessary preliminary evidence to demonstrate the application of the drug, riluzole, for treatment of this debilitating and irreversible disorder.
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