title: PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia.
abstract: Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery, or postdelivery respiratory management. The sole approved treatment for acute stroke is tissue type plasminogen activator. H/I impairs pial artery dilation (PAD) induced by hypercapnia and hypotension, the impairment aggravated by type plasminogen activator and attenuated by the plasminogen activator inhibitor-1-derived peptide EEIIMD. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is upregulated after H/I and ERK contribute to impaired cerebrovasodilation. This study determined the roles of p38 and JNK MAPK in the impairment of dilation post-H/I in pigs equipped with a closed cranial window and the relationship between alterations in MAPK isoforms and EEIIMD-mediated cerebrovascular protection. Cerebrospinal fluid-phosphorylated (activated) p38 MAPK, but not JNK MAPK, was increased after H/I, an effect potentiated by intravenous EEIIMD administered 1 h postinjury. PAD in response to hypercapnia and hypotension was blunted by H/I, but dilation was maintained by EEIIMD. PAD 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 postinjury treatment with EEIIMD attenuated impaired cerebrovasodilation post-H/I by upregulating p38 but not JNK. These data suggest that plasminogen activator inhibitor-1-based peptides and other approaches to upregulate p38 may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy for diverse central nervous system disorders associated with H/I.
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA. armsteaw@uphs.upenn.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: J Willis
authors.initials: JW
authors.lastname: Kiessling
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D006935:Hypercapnia / Q000201:enzymology / Q000503:physiopathology; D007022:Hypotension / Q000201:enzymology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007275:Injections, Intravenous; D007545:Isoproterenol / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D010841:Pia Mater / Q000098:blood supply*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid*
chemical_list: D000873:Anthracenes; D002317:Cardiovascular Agents; D007093:Imidazoles; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014665:Vasodilator Agents; C513663:glutamyl-glutamyl-isoleucyl-isoleucyl-methionyl-aspartic acid; D002245:Carbon Dioxide; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D007545:Isoproterenol; C093642:SB 203580