Discovery has been made (patent filed) only naturally occuring (2S, 3R) isoforms of net cationic 1-0-sphingosylphosphorylcholine (lysosphingomyelin) and 1-O-sphingosylmonoglycoside (lysocarabroside) are specific amphiphilic modulators of catalytic regulatory domains of neuronal beta, delta, and gamma-phospholnositidase-C. Phosphoinosltidase-C-linked metabotropic M1 and M5 glutamate receptors enhance release of CA++- mobilizing inositol trisphosphate from the lipid substrate phosphatidylinositol bisphosphate by the agency of this enzyme. Glutamate excitotoxicity resulting from excessive activation of those receptors produces in major part the prolonged heightened CA++-signalling that destabilizes the neuronal cytoskeletal apparatus and causes CA++-activated neuronal protease, DNAase and phospholipase destruction during brain stroke (anoxia/ischemia), seizure, and Alzheimer's disease. This 6-month Phase i SBIR project will carefully a) validate a metabotrophic glutamatergic neuronal culture model for In vitro study; b) quantitate endogenous neuronal levels and experimental exogenous enrichment levels of lysosphingomyelin and lysocerebroside; c) determine parameters of lyso- sphingomyelin/lysocerebroside exposure needed to down-titrate inositol trisphosphate release and intraneuronal CA++ levels during excessive M1 /M5 metabotropic glutamate receptor stimulation; d) determine non-toxic ranges for neuronal lysosphingomyelin and lysocerebroside levels. The data will be applicable to subsequent Phase II application for in vivo whole animal studies. Commercial applicability may include licensing for 1) research tool use with animal models; 2) eventual human disease control.Proposed commercial application:The research attempts to provide a commercially valuable research and human disease control tool for regulation of glutamate-excititoxic neuron destruction. Unlike current methods, at the approach is to regulate a branch of the metabotropic glutamate cascade mechanism without disrupting vital inotropic glutamate receptor activity, using non-toxic naturally occuring regulatory compounds.National Institute on Drug Abuse (NIDA)
