NEUROPROTECTIVE STRATEGIES IN A MODEL OF CHRONIC GLUTAMATE-MEDIATED MOTOR-NEURON TOXICITY

A dramatic loss of glutamate transport has been observed in sporadic a myotrophic lateral sclerosis and has been postulated to contribute to the disease. Experimentally, this hypothesis was corroborated by mimic king the chronic loss of glutamate transport in postnatal rat spinal c ord organotypic cultures through the use of glutamate transport inhibi tors. This system is characterized by a relatively selective slow loss of ventral horn motor neurons resulting from glutamate transport inhi bition, In this study, spinal cord organotypic cultures were used to t est various drugs to evaluate their neuroprotective properties against this slow glutamate-mediated neurotoxicity, The most potent neuroprot ectants were drugs that altered glutamate neurotransmission, including non-NMDA receptor antagonists (GYKI-52466, PD144216, and PD139977) an d drugs that could block presynaptic release or synthesis (riluzole an d gabapentin). In addition, some antioxidants (U83836E and N-t-bulyl-a lpha-phenylnitrone) and inhibitors of nitric oxide synthesis (N-G-mono methyl-L-arginine acetate) were modestly neuroprotective. The calcium endonuclease inhibitor aurintricarboxylic acid and the calcium release inhibitor dantrolene also provided partial motor neuron protection, H owever, several antioxidants and calcium channel antagonists had no ex citotoxic neuroprotectant activity. This system provides a preclinical screening method for the burgeoning number of drugs postulated for cl inical trials in motor neuron disease and a model to evaluate the mech anisms of chronic glutamate toxicity.