Novel glutamate receptor antagonists selectively protect against kainic acid neurotoxicity in cultured cerebral cortex neurons.
The effect on excitatory amino acid (EAA)-induced toxicity of two novel non-N-methyl-D-aspartate (non-NMDA) antagonists 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid (AMOA) and 2-amino-3-[2-(3-hydroxy-5-methyl-isoxazol-4-yl)methyl-5-methyl-3- oxoisoxazolin-4-yl]propionic acid (AMNH) was tested in primary cultures of cerebral cortex neurons. Such cultures provide a useful model for the investigation of the toxicity of EAAs and a convenient screening system for potential neuroprotective activity of pharmacological agents. It was demonstrated that AMNH and AMOA abolished neurotoxicity induced by kainic acid with IC50 values of 62 +/- 10 and 120 +/- 19 microM, respectively. No effect on neuronal damage induced by NMDA or AMPA could be detected.
Frandsen
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Department of Biology, Royal Danish School of Pharmacy, Copenhagen.
Krogsgaard-Larsen
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Schousboe
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D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007555:Isoxazoles / Q000494:pharmacology*; D007608:Kainic Acid / Q000506:poisoning*; D009474:Neurons / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology*; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D007555:Isoxazoles; D011422:Propionates; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; C066116:2-amino-3-(3-(carboxymethoxy)-5-methylisoxazol-4-yl)propionic acid; C066117:2-amino-3-(2-(3-hydroxy-5-methylisoxazol-4-yl)methyl-5-methyl-3-oxoisoxazolin-4-yl)propionic acid; D018698:Glutamic Acid; D007608:Kainic Acid