Anticonvulsant Activity of Glycylglycine and δ‐Aminovaleric Acid: Evidence for Glutamine Exchange in Amino Acid Transport

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Abstract
We have proposed that glutamine serves in a facilitated diffusion process, mediated by the enzyme γ‐glutamyl transferase (γ‐glutamyl transpeptidase; γGT) and that it leaves the brain in exchange for entering amino acids. Glutamine is also a precursor of γ‐aminobutyric acid (GABA). Thus, providing an alternate substrate for γGT should spare brain glutamine, raise GABA, and cause an anticonvulsant effect. We have found that glycylglycine, the best‐known substrate for γGT, and δ‐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 electroconvul‐sive 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 γGT 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. Key Words: Amino acids, transport—γ‐Aminobutyric acid—δ‐Amino valeric acid—Anticonvulsant—Glutamine, exchange—Seizures.