The non-competitive AMPA antagonist LY 300168 (GYKI 53655) attenuates AMPA-induced hippocampal injury in neonatal rodents.
In contrast with the neuroprotective efficacy of competitive and non-competitive N-methyl-D-aspartate (NMDA) antagonists versus NMDA neurotoxicity, reported neuroprotective effects of non-NMDA antagonists in limiting alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) toxicity have been less robust. We tested the effect of the non-competitive AMPA receptor antagonist LY 300168 (GYKI 53655; E. Lilly) (0.25 or 2.5 mg/kg per dose i.p. x 3 doses vs. vehicle) on AMPA-induced excitotoxic injury in postnatal day 7 (P7) rats. To assess specificity, we tested the effect of LY 300168 (2.5 mg/kg per dose x 3 doses) on NMDA-induced excitotoxic injury. P7 rats received right intrahippocampal injections of either (S)-AMPA (2.5 nmol, n = 67) or NMDA (12.5 nmol, n = 11). Injection of AMPA resulted in right hippocampal atrophy with pyramidal cell loss. LY 300168 treatment produced dose-dependent attenuation of AMPA-induced right hippocampal injury; based on comparisons with left hippocampal volumes, 2.5 nmol AMPA resulted in 42 +/- 3% (mean +/- SEM) right hippocampal volume loss in controls, but only 10 +/- 5% after LY 300168 2.5 mg/kg per dose (P < 0.001; ANOVA). LY 300168 had no effect on NMDA-induced hippocampal injury. The data support the hypothesis that drugs that allosterically regulate AMPA receptor activity can modulate the response of immature brain to AMPA-mediated injury.
Liu
X H
XH
Department of Pediatrics, University of Michigan Medical Center, Ann Arbor 48109-0646, USA.
Wang
P
P
Barks
J D
JD
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000139:chemically induced / Q000517:prevention & control*; D001569:Benzodiazepines / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries / Q000473:pathology*; D007274:Injections, Intraperitoneal; D016202:N-Methylaspartate / Q000008:administration & dosage; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D001569:Benzodiazepines; C079692:GYKI 53655; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid