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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021019-03
Application #
3401742
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-08-01
Project End
1991-01-31
Budget Start
1988-08-01
Budget End
1991-01-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Chang, Y F; Gao, X M (1995) L-lysine is a barbiturate-like anticonvulsant and modulator of the benzodiazepine receptor. Neurochem Res 20:931-7
Chang, Y F; Wang, Y; Cauley, R K et al. (1993) Chronic L-lysine develops anti-pentylenetetrazol tolerance and reduces synaptic GABAergic sensitivity. Eur J Pharmacol 233:209-17
Rao, V V; Pan, X; Chang, Y F (1992) Developmental changes of L-lysine-ketoglutarate reductase in rat brain and liver. Comp Biochem Physiol B 103:221-4
Rao, V V; Chang, Y F (1992) Assay for L-pipecolate oxidase activity in human liver: detection of enzyme deficiency in hyperpipecolic acidaemia. Biochim Biophys Acta 1139:189-95
Chang, Y F; Gao, X M; Chen, J S (1991) Correlation between enhancement of [3H]flunitrazepam binding and suppression of pentylenetetrazol-induced seizures by L-lysine. Eur J Pharmacol 193:239-47
Chang, Y F; Ghosh, P; Rao, V V (1990) L-pipecolic acid metabolism in human liver: L-alpha-aminoadipate delta-semialdehyde oxidoreductase. Biochim Biophys Acta 1038:300-5
Rao, V V; Chang, Y F (1990) L-pipecolic acid metabolism in human liver: detection of L-pipecolate oxidase and identification of its reaction product. Biochim Biophys Acta 1038:295-9
Gao, X M; Chang, Y F (1989) Enhancement of benzodiazepine receptor binding by L-lysine is chloride-dependent and due to increase in binding affinity. Eur J Pharmacol 173:197-200
Chang, Y F; Hargest, V; Chen, J S (1988) Modulation of benzodiazepine by lysine and pipecolic acid on pentylenetetrazol-induced seizures. Life Sci 43:1177-88