Anticonvulsant dicarboxyphenylglycines differentially modulate excitatory amino acid release in the rat cerebral cortex

• Published in: Brain research 2003-07, Vol.977 (1), p.119-123
• Main Authors: Lee, J.J., Jane, D.E., Croucher, M.J.
• Format: Article
• Language: English
• Subjects: 3,4-Dicarboxyphenylglycines; [ 3H] d-aspartate release; Animals; Anticonvulsant; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Aspartic Acid - analysis; Aspartic Acid - metabolism; Benzoates - pharmacology; Biological and medical sciences; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebrocortical minislice; Dicarboxyphenylglycine; Dose-Response Relationship, Drug; Excitatory Amino Acids - analysis; Excitatory Amino Acids - metabolism; Glutamic Acid - analysis; Glutamic Acid - metabolism; Glycine - analogs & derivatives; Glycine - pharmacology; In Vitro Techniques; Male; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Potassium Chloride - pharmacology; Protein Isoforms - pharmacology; Rats; Rats, Sprague-Dawley; Tritium - metabolism
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(03)02657-X

The 3,4-dicarboxyphenylglycines (3,4-DCPGs) have recently been shown to be effective new anticonvulsant agents in a rodent model of epilepsy, with the racemic mixture showing significantly greater potency than either isomer alone. The ( R)-isomer has been identified as a competitive AMPA-type ionotropic glutamate receptor antagonist, whilst ( S)-3,4-DCPG is a highly potent and selective metabotropic glutamate receptor 8 (mGlu8 receptor) agonist. We now report the inhibitory activity of ( R)- and ( RS)-3,4-DCPG, but not ( S)-3,4-DCPG, against both 35 mM and 50 mM KCl-evoked glutamate release in the rat cerebral cortex in vitro. In contrast to the anticonvulsant actions of the 3,4-DCPGs, no evidence was obtained for a synergistic inhibitory interaction between the separate isomers. We conclude that whilst inhibition of cortical excitatory amino acid release may contribute to the anticonvulsant actions of ( RS)-3,4-DCPG, it does not represent the sole mechanism of action. Synergistic interactions between ligands acting at different subtypes of ionotropic and metabotropic glutamate receptors remains a promising new strategy for the treatment of currently drug-refractory seizure states.