Perinatal hypoxic-ischemic brain injury enhances quisqualic acid-stimulated phosphoinositide turnover.
In an experimental model of perinatal hypoxic-ischemic brain injury, we examined quisqualic acid (Quis)-stimulated phosphoinositide (PPI) turnover in hippocampus and striatum. To produce a unilateral forebrain lesion in 7-day-old rat pups, the right carotid artery was ligated and animals were then exposed to moderate hypoxia (8% oxygen) for 2.5 h. Pups were killed 24 h later and Quis-stimulated PPI turnover was assayed in tissue slices obtained from hippocampus and striatum, target regions for hypoxic-ischemic injury. The glutamate agonist Quis (10(-4) M) preferentially stimulated PPI hydrolysis in injured brain. In hippocampal slices of tissue derived from the right cerebral hemisphere, the addition of Quis stimulated accumulation of inositol phosphates by more than ninefold (1,053 +/- 237% of basal, mean +/- SEM, n = 9). In contrast, the addition of Quis stimulated accumulation of inositol phosphates by about fivefold in the contralateral hemisphere (588 +/- 134%) and by about sixfold in controls (631 +/- 177%, p less than 0.005, comparison of ischemic tissue with control). In striatal tissue, the corresponding values were 801 +/- 157%, 474 +/- 89%, and 506 +/- 115% (p less than 0.05). In contrast, stimulation of PPI turnover elicited by the cholinergic agonist carbamoylcholine, (10(-4) or 10(-2) M) was unaffected by hypoxia-ischemia. The results suggest that prior exposure to hypoxia-ischemia enhances coupling of excitatory amino acid receptors to phospholipase C activity. This activation may contribute to the pathogenesis of irreversible brain injury and/or to mechanisms of recovery.
Chen
C K
CK
Department of Pediatrics, University of Michigan Medical School, Ann Arbor 48104-1687.
Silverstein
F S
FS
Fisher
S K
SK
Statman
D
D
Johnston
M V
MV
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005311:Fetal Hypoxia / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011247:Pregnancy; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D010069:Oxadiazoles; D010716:Phosphatidylinositols; D016318:Quisqualic Acid