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

Abstract

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.