Neuroprotective synergism of 2-amino-3-phosphonoproprionate (D,L-AP3) and MK-801 against ibotenate induced brain injury.
The neuroprotective characteristics of the functional antagonist of metabotropic stimulated phosphoinositide hydrolysis, 2-amino-3-phosphonoproprionate (D,L-AP3), were examined alone and in combination with the non-competitive N-methyl-D-aspartate (NMDA) antagonist, MK-801, against ibotenate induced brain injury. Postnatal day (PND) 7 rats received unilateral stereotaxic intrastriatal injections of 10 nmol ibotenate and treated with either D,L-AP3 (600 nmol i.c.), MK-801 (1 mg/kg i.p.) or both. The severity of brain injury was assessed on PND 12 by comparison of the weights of injected and contralateral cerebral hemispheres. Ibotenate induced injury was partially reduced by treatment with MK-801 (34.0 +/- 4.4% protection, P < 0.05 vs. PBS treated, independent t-test) but not D,L-AP3. However, combined treatment with both MK-801 and D,L-AP3 produced marked synergistic neuroprotection (83.5 +/- 7.6% protection, P < 0.001 vs. PBS treated, independent t-test). The data suggest that metabotropic stimulated phosphoinositide hydrolysis contributes to excitotoxic neuronal injury in the presence of concurrent ionotropic receptor activation.
McDonald
J W
JW
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
Johnston
M V
MV
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain; D001927:Brain Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D007051:Ibotenic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007267:Injections; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D011810:Quinoxalines; C000211:2-amino-3-phosphonopropionic acid; D007051:Ibotenic Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000409:Alanine