PAI‐1 derived peptide EEIIMD prevents impairment of hypercapnic and hypotensive cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

Abstract

Babies are frequently exposed to hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery or post delivery respiratory management. The sole approved treatment for acute stroke is tissue type plasminogen activator (tPA). H/I impairs pial artery dilation (PAD) to hypercapnia and hypotension, tPA aggravates impairment, and the PAI‐1 derived peptide EEIIMD largely prevents it. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is upregulated after H/I and ERK contributes to impaired cerebrovasodilation. This study determined the roles of p38 and JNK MAPK in H/I dilator impairment in piglets equipped with a closed cranial window. CSF phosphorylated (activated) p38 MAPK but not JNK MAPK was elevated by H/I, an effect potentiated by EEIIMD. Hypercapnic and hypotensive PAD was blunted by H/I but dilation was maintained by EEIIMD. Hypercapnic and hypotensive PAD after H/I was further impaired by the p38 antagonist SB 203580, but unchanged by the JNK antagonist SP 600125. Isoproterenol induced PAD was unchanged by H/I, EEIIMD, SB 203580, and SP 600125. These data indicate that EEIIMD limits H/I cerebrovasodilator impairment through upregulation of p38 but not JNK. These data suggest that p38 upregulation may offer a novel approach to increase the benefit/risk ratio of thrombolytic therapy for CNS disorders associated with hypoxia/ischemia.