ACUTE BRAIN INJURY, MECHANISMS AND PROTECTION

Washington University, Saint Louis MO

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Abstract

Acute brain injury conditions such as ischemia and head trauma are thought to be triggered by an excitotoxic process involving excessive activation of glutamate receptors. In the infant rat brain, evidence implicating the NMDA subtype of glutamate receptor is particularly strong. It has also been reported, but is less well established, that mechanisms associated with programmed cell death may play a role. The applicant has undertaken a systematic investigation of the role of excitotoxicity and programmed cell death in acute brain injury conditions. Initially, the applicant performed an ultrastructural analysis of physiological cell death (PCD) that occurs naturally in the developing CNS, and compared this process with three conditions that are generally considered examples of excitotoxicity, namely acute neuro- degeneration induced in the infant rat brain by hypoxia/ischemia, head trauma or by systemic administration of glutamate. This analysis revealed that PCD is characterized by ultrastructural changes that have a distinctive appearance and occur in a distinctive sequence, and that the three examples of excitotoxicity appeared identical to one another but were very different from the PCD process. In addition, the three examples of excitotoxicity can be prevented by drugs that block NMDA glutamate receptors. This evaluation pertains only to the acute neurodegenerative process that occurs within a 6 hr period following hypoxia/ischemia or head trauma, and in the case of head trauma the excitotoxic damage was observed only at the site of impact. The applicant recently examined the brains of infant rats at later intervals following head trauma, and found striking evidence for a delayed neurodegenerative reaction that evolves over a 6 to 24 hr period at a distance from the impact site and has all of the distinctive ultrastructural characteristics of a PCD process. Although treatment with an NMDA antagonist protected against the acute excitotoxic lesion at the impact site, this mode of treatment appeared to increase the severity of the distant, delayed PCD lesion. The aims of the present application are to study the mechanisms responsible for and methods that can protect against the delayed trauma-induced PCD-like lesion, and to determine whether ischemic neurodegeneration in the infant rat brain also has a delayed PCD-like component. The long term goals are to clarify the underlying mechanisms and develop improved methods of treating human pediatric acute brain injury conditions.