Ischemic Injury and Neuroprotection in the Immature Brain

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DESCRIPTION (provided by applicant): The career objective of this proposal is to permit the candidate, an academic child neurologist and recipient of a NINDS Neurological Scientist Academic Development Award (K12), to establish an independent research program in ischemic injury and neuroprotection in the immature brain. This Award would permit the candidate to characterize a highly promising animal model of stroke in the immature brain, develop expertise in endogenous stem cell proliferation after ischemia, and to gain facility in carrying out rigorous mouse trials of neuroprotection with anticonvulsants. Stroke in the term neonate or infant is an important cause of neurologic morbidity. Dr. Comi has developed a new immature mouse model of stroke utilizing unilateral carotid ligation alone to produce infarcts in immature mice. The vulnerability to injury varies with strain and age at surgery. We have shown in this model that dextromethorphan, an NMDA receptor antagonist with anticonvulsant actions, is neuroprotective. This research addresses the hypothesis that anticonvulsants will attenuate ischemic brain injury in the immature brain. The candidate's long term goal is rigorous pursuit of preclinical screening of neuroprotective strategies for ischemic injury in the developing brain and enhancement of the endogenous stem cell response after injury. The Specific Aims are to: 1) Characterize the evolution of brain injury and endogenous stem cell proliferation after unilateral carotid ligation. 2) Determine the extent of anticonvulsant neuroprotection. Stroke in the developing brain is an important cause of neurologic impairment that often persists into adulthood. An intervention providing even partial reduction of neurologic impairments would result in significant benefit both in terms of quality of life and decreased national healthcare costs. This work will provide important insights into the brain injury and regenerative response after stroke in this new immature mouse model and will test neuroprotective interventions with relevance to this population.