N-methyl-D-aspartate-mediated injury enhances quisqualic acid-stimulated phosphoinositide turnover in perinatal rats.

Abstract

Previous work in our laboratory demonstrated that ischemic-hypoxic brain injury in postnatal day 7 rats causes a substantial increase in phosphoinositide (PPI) turnover stimulated by the glutamate analogue quisqualic acid (QUIS) in the hippocampus and striatum. To examine this phenomenon in more detail, we performed similar experiments after producing injury by unilateral intracerebral injections of the glutamate analogue N-methyl-D-aspartate (NMDA). The 7-day-old rodent brain is hypersensitive to NMDA neurotoxicity and NMDA injection causes histopathology that closely resembles that produced by ischemia-hypoxia. NMDA, 17 nmol in 0.5 microliter, was injected into the right posterior striatum of 7-day-old rat pups and they were killed 3 days later. Hippocampal or striatal tissue slices were prepared from ipsilateral and contralateral hemispheres from vehicle-injected control and from noninjected control rat pups. Slices were then incubated with myo-[3H]inositol plus glutamate agonists or antagonists in the presence of lithium ions and [3H]inositol monophosphate ([3H]IP1) accumulation was measured. The glutamate agonists, QUIS, L-glutamic acid, and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, stimulated greater [3H]IP1 release in tissue ipsilateral to the NMDA injection compared with that in the contralateral side and in control pups. The glutamate antagonists, D,L-2-amino-7-phosphonoheptanoic acid, 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphoric acid, kynurenic acid, and 6,7-dinitroquinoxaline-2,3-dione did not inhibit QUIS-stimulated [3H]IP1 release. The enhanced PPI turnover in the lesioned tissue was specific to glutamate receptors because carbachol (CARB) failed to elicit preferential enhanced stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)