RBC-coupled tPA prevents cerebrovasodilatory impairment and tissue injury in pediatric cerebral hypoxia/ischemia through inhibition of ERK MAPK unregulation

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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 tPA to RBCs reduces its CNS toxicity through spatially confining the drug to the vasculature. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, is upregulated after H/I. In this study we determined if RBC-tPA given before or after cerebral H/I would preserve responses to cerebrovasodilators and prevent neuronal injury ... continued below

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Ganguly, Kumkum; Armstead, William M; Kiessling, J W; Chen, Xiao - Han; Smith, Douglas H; Higazi, Abd Ar et al. January 1, 2008.

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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 tPA to RBCs reduces its CNS toxicity through spatially confining the drug to the vasculature. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, is upregulated after H/I. In this study we determined if RBC-tPA given before or after cerebral H/I would preserve responses to cerebrovasodilators and prevent neuronal injury mediated through the ERK MAPK pathway. Animals given RBC-tPA maintained responses to cerebrovasodilators at levels equivalent to pre-H/I values. CSF and brain parenchymal ERK MAPK was elevated by H/I and this upregulation was potentiated by tPA, but blunted by RBC-tPA. U 0126, an ERK MAPK antagonist, also maintained cerebrovasodilation post H/I. Neuronal degeneration in CA1 hippocampus and parietal cortex after H/I was exacerbated by tPA, but ameliorated by RBC-tPA and U 0126. These data suggest that coupling tPA to RBCs may offer a novel approach towards increasing the benefit/risk ratio of thrombolytic therapy for CNS disorders associated with H/I.

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  • Journal Name: Nature Neuroscience

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  • Report No.: LA-UR-08-08052
  • Report No.: LA-UR-08-8052
  • Grant Number: AC52-06NA25396
  • Office of Scientific & Technical Information Report Number: 956676
  • Archival Resource Key: ark:/67531/metadc930676

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Reports, articles and other documents harvested from the Office of Scientific and Technical Information.

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  • January 1, 2008

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  • Nov. 13, 2016, 7:26 p.m.

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  • Dec. 12, 2016, 4:46 p.m.

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Ganguly, Kumkum; Armstead, William M; Kiessling, J W; Chen, Xiao - Han; Smith, Douglas H; Higazi, Abd Ar et al. RBC-coupled tPA prevents cerebrovasodilatory impairment and tissue injury in pediatric cerebral hypoxia/ischemia through inhibition of ERK MAPK unregulation, article, January 1, 2008; [New Mexico]. (digital.library.unt.edu/ark:/67531/metadc930676/: accessed April 22, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.