The Role of Glutamate Neurotoxicity in Hypoxic-Ischemic Neuronal Death

Abstract

Dennis W. ChoiDepartment of Neurology, Stanford University, Stanford,California 94305Steven M. RothmanDepartments of Pediatrics, Neurology, and Anatomy and Neurobiology,Washington University, St. Louis, Missouri 63110The human brain depends on its blood supply for a continuous supply ofoxygen and glucose. Irreversible brain damage occurs if blood flow isreduced below about 10 ml/100 g tissue/min and if blood flow is completelyinterrupted, damage will occur in only a few minutes. Unfortunately, suchreductions (ischemia) are common in disease states: either localized individual vascular territories, as in stroke; or globally, as in cardiac arrest.Cerebral hypoxia can also occur in isolation, for example in respiratoryarrest, carbon monoxide poisoning, or near-drowning; pure glucose depri-vation can occur in insulin overdose or a variety of metabolic disorders.As a group, these disorders are a leading cause of neurological disabilityand death; stroke alone is the third most common cause of death in NorthAmerica.Despite its clinical importance, little is known about the cellular patho-genesis of hypoxic-ischemic brain damage, and at present there is noeffective therapy. A critical question has been why brain, more than mostother tissues, is so vulnerable to hypoxic-ischemic insults. In particular,certain neuronal subpopulations, such as hippocampal field CA1 andneocortical layers 3, 5, and 6, are characteristically destroyed after sub-maximal hypoxic-ischenfic exposure. A possible answer has emerged inthe last few years: At least some of this special vulnerability may beaccounted for by the central neurotoxicity of the endogenous excitatory1710147-006X/90/0301 ~:1171 $02.00www.annualreviews.org/aronline Annual Reviews