A research project is proposed to investigate the antiepileptic activity of lysine and its metabolic intermediates and their esters. An animal model will be used for the convulsion study. Specific chemoconvulsants (i.e., picrotoxin, bicuculline, pentylenetetrazole and isoniazid) will be used to induce seizures in mice. The anticonvulsant activity will be measured by the dose-response curve technique. Neurotoxicity of lysine metabolites will also be assessed in order to estimate the therapeutic index (TD50/ED50). The effect of lysine metabolites on the binding of benzodiazepine, Gamma-aminobutyric acid (GABA) and picrotoxin receptors will be studied both in vitro and in vivo in order to understand the molecular mechanism involved in the antiepileptic activity of lysine metabolites. The effect of lysine metabolites on the re-uptake and release of GABA will be studied with synaptosomes and glial cells. The effect of lysine metabolic intermediates on GABA level and glutamic acid decarboxylase and Gamma-aminobutyrate-Alpha-keto-glutarate aminotransferase activities will be studied in the absence or presence of seizures induced by convulsants. It is hoped that this research work will identify the effective antiepileptic lysine metabolites and their esters which may lead to improved effectiveness of seizure treatment in the human and minimize the risk (toxicity) of this treatment. It is also hoped that this research work will help understand the anticonvulsant mechanism of lysine and its metabolites, and its relationship with the GABA system in epileptogenesis which may lead to the design and development of more effective and safer antiepileptics for seizure treatment in the human.
