Chronic ethanol ingestion results in neurodegeneration with loss of neurons, glial proliferation and enlargements in ventricular and subarachnoid space. Work from our laboratories has demonstrated that chronic ethanol administration to animals produces an up-regulation of the excitatory N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in brain. We have recently implicated the NMDA receptor system in induction of excitotoxic damage to various neurons of the brain during ethanol withdrawal. In this Phase I SBIR proposal, we wish to test a series of compounds for their effectiveness in protecting neurons of the cerebellum and cerebral cortex, grown in culture, against ethanol withdrawal induced excitotoxic damage. We will assess the effectiveness of a novel NMDA receptor channel blocker, (+)-5- aminocarbonyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine(ADCI), which we have previously shown to be an excellent agent for reducing behavioral hyperexcitability (tremor, convulsions) during ethanol withdrawal in animals. We will also test antagonists, i.e.,: cycloleucine, and low efficacy partial agonists i.e.,; 1-neuroprotective actions in our cell culture model of ethanol withdrawal excitotoxicity. Finally, we will test a series of gangliosides, including GM1 and GT1b, since these compounds have been touted to protect against glutamate-induced excitotoxicity without compromising the initial neurotransmission related events accompanying NMDA receptor stimulation. Our studies will generate an understanding of which classes of compounds are most effective for preventing ethanol withdrawal excitotoxicity and provide a basis for in vivo studies with animals in Phase II of the SBIR program.
