Anticonvulsant activity of glycylglycine and delta-aminovaleric acid: evidence for glutamine exchange in amino acid transport.
We have proposed that glutamine serves in a facilitated diffusion process, mediated by the enzyme gamma-glutamyl transferase (gamma-glutamyl transpeptidase; gamma GT) and that it leaves the brain in exchange for entering amino acids. Glutamine is also a precursor of gamma-aminobutyric acid (GABA). Thus, providing an alternate substrate for gamma GT should spare brain glutamine, raise GABA, and cause an anticonvulsant effect. We have found that glycylglycine, the best-known substrate for gamma GT, and delta-aminovaleric acid (DAVA), a structural analog, have anticonvulsant activity in DBA/2J mice. Both compounds can decrease the incidence and severity of seizures induced by L-methionine-RS-sulfoximine or electroconvulsive shock. DAVA was also tested and found to be active against seizures caused by pentylenetetrazol or picrotoxin. [14C]DAVA entered the brain at the rate of 18.7 nmol/g/min. The activity of DAVA as a substrate of gamma GT was intermediate to that of glycylglycine and glutamine. Preliminary studies have shown that brain glutamine and perhaps GABA are elevated 3 h after administration of DAVA (7.5 mmol/kg). These findings support the theory that glutamine exchange plays a role in amino acid transport across the blood-brain barrier and suggests a new concept in anticonvulsant therapy.
D000596:Amino Acids / Q000378:metabolism* / Q000494:pharmacology*; D021542:Amino Acids, Neutral; D000818:Animals; D000927:Anticonvulsants; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D004597:Electroshock; D005260:Female; D005973:Glutamine / Q000378:metabolism*; D006033:Glycylglycine / Q000494:pharmacology*; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009132:Muscles / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology
D000596:Amino Acids; D021542:Amino Acids, Neutral; D000927:Anticonvulsants; D004151:Dipeptides; D005973:Glutamine; D006033:Glycylglycine; C013809:5-aminovaleric acid