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However, tPA potentiates H\/I-induced impairment of responses to cerebrovasodilators such as hypercapnia and hypotension, and blockade of tPA-mediated vasoactivity prevents this deleterious effect. Coupling of tPA to red blood cells (RBCs) reduces its central nervous system (CNS) toxicity through spatially confining the drug to the vasculature. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, is upregulated after H\/I. In this study we determined whether RBC-tPA given before or after cerebral H\/I would preserve responses to cerebrovasodilators and prevent neuronal injury mediated through the extracellular signal-related kinase (ERK) MAPK pathway. Animals given RBC-tPA maintained responses to cerebrovasodilators at levels equivalent to pre-H\/I values. cerebrospinal fluid and brain parenchymal ERK MAPK was elevated by H\/I and this upregulation was potentiated by tPA, but blunted by RBC-tPA. U0126, an ERK MAPK antagonist, also maintained cerebrovasodilation post H\/I. Neuronal degeneration in CA1 hippocampus after H\/I was not improved by tPA, but was ameliorated by RBC-tPA and U0126. These data suggest that coupling of tPA to RBCs offers a novel approach toward increasing the benefit\/risk ratio of thrombolytic therapy for CNS disorders associated with H\/I.<\/jats:p>","DOI":"10.1038\/jcbfm.2009.61","type":"journal-article","created":{"date-parts":[[2009,5,13]],"date-time":"2009-05-13T04:00:16Z","timestamp":1242187216000},"page":"1463-1474","source":"Crossref","is-referenced-by-count":34,"title":["Red Blood Cells-Coupled tPA Prevents Impairment of Cerebral Vasodilatory Responses and Tissue Injury in Pediatric Cerebral Hypoxia\/Ischemia through Inhibition of ERK MAPK Activation"],"prefix":"10.1177","volume":"29","author":[{"given":"William M","family":"Armstead","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, 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