Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 29, Issue 8, Pages 1463-1474Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2009.61
Keywords
newborn; cerebral circulation; stroke; tPA
Categories
Funding
- NCI NIH HHS [CA83121, R01 CA083121] Funding Source: Medline
- NHLBI NIH HHS [HL81864, T32 HL007971, HL090697, HL77760, HL76406, R01 HL077760, HL82545, R01 HL076206, P01 HL076406, HL66442, R01 HL090697, R01 HL066442, HL76206, R01 HL090697-01A1, R21 HL081864, HL07971] Funding Source: Medline
- NICHD NIH HHS [HD57355, R01 HD057355] Funding Source: Medline
- NINDS NIH HHS [NS53410, R01 NS053410] Funding Source: Medline
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Babies experience hypoxia (H) and ischemia (I) from stroke. The only approved treatment for stroke is fibrinolytic therapy with tissue-type plasminogen activator (tPA). 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. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1463-1474; doi: 10.1038/jcbfm.2009.61; published online 13 May 2009
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