Plasminogen activators and cerebral ischemic injury

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DESCRIPTION (provided by applicant): Babies are frequently exposed to hypoxia and ischemia during the perinatal period due to stroke or problems with delivery or respiratory management post delivery. Neonatal stroke incidence can be as high as 1 in 4000 births. One contributor to neurologic damage is cerebrovascular dysfunction. The only FDA approved treatment for acute stroke is the administration of tPA. Nonetheless, in basic science studies, tPA has been observed to exhibit a dual beneficial/deleterious effect. In addition to its salutary role in reperfusion, tPA may contribute to neuronal cell death. A potential explanation for the tPA therapeutic treatment paradox could relate to the vascular activity (dilation) of tPA. The term neurovascular unit (NVU) focuses attention on the interactions between cerebral blood vessels and neurons. Mitogen activated protein kinase (MAPK) expression is enhanced after cerebral ischemia and may be one of the most distal systems affecting both the vasculature and genomics. The hypothesis is that plasminogen activator production following cerebral hypoxia/ischemia contributes to impaired cerebral hemodynamics and neuronal cell loss post insult. Plasminogen activators are hypothesized to impair reactivity to vascular stimuli and produce hyperemia which results in edema causing neuronal cell loss. Dynamic interactions between cerebral blood vessels and neurons thus result in an integrated response to the insult, consistent with the NVU concept. To address this hypothesis, three specific aims will be pursued in newborn pigs: 1. Characterize the relationship between plasminogen activators and cerebral hemodynamics after hypoxia/ischemia, 2. Investigate the role of MAPK as the mechanism by which plasminogen activators control cerebral hemodynamics post insult; Changes in the MAPK isoform expression profile result in impaired cerebral hemodynamics and neuron cell loss. 3. Determine the association between impaired cerebral hemodynamics and histopathology post insult. The closed cranial window technique will be used to measure pial artery diameter and determine CSF plasminogen activator concentration via ELISA. CBF will be determined by the radiolabeled microsphere method. Immunohistochemistry and techniques for detection of plasminogen activator and MAPK expression will be used to achieve an integrated whole animal/molecular perspective on the relationship between plasminogen activators, cerebral hemodynamics, and histopathology.