Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Armstead, W.M. et al.

William M. Armstead, Kumkum Ganguly, John W. Kiessling, Xiao-Han Chen, Douglas H. Smith, Abd A. R. Higazi, Douglas B. Cines, Khalil Bdeir, Sergei Zaitsev, Vladimir R. Muzykantov,

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.

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.[1]

References

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. Armstead, W.M., Ganguly, K., Kiessling, J.W., Chen, X.H., Smith, D.H., Higazi, A.A., Cines, D.B., Bdeir, K., Zaitsev, S., Muzykantov, V.R. J. Cereb. Blood Flow Metab. (2009) [Pubmed]

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