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: William M Armstead, John Riley, J Willis Kiessling, Douglas B Cines, Abd Al-Roof Higazi
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 299 Issue 1 Pg. H76-80 (Jul 2010) ISSN: 1522-1539 [Electronic] United States
• PMID: 20435843 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Cardiovascular Agents
• Imidazoles
• Oligopeptides
• Protein Kinase Inhibitors
• Pyridines
• Vasodilator Agents
• glutamyl-glutamyl-isoleucyl-isoleucyl-methionyl-aspartic acid
• Carbon Dioxide
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Isoproterenol
• SB 203580

Topics

• Animals
• Animals, Newborn
• Anthracenes (pharmacology)
• Blood Pressure (drug effects)
• Carbon Dioxide (blood)
• Cardiovascular Agents (administration & dosage, pharmacology)
• Cerebrovascular Circulation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Activation
• Female
• Hypercapnia (enzymology, physiopathology)
• Hypotension (enzymology, physiopathology)
• Hypoxia-Ischemia, Brain (drug therapy, enzymology, physiopathology)
• Imidazoles (pharmacology)
• Injections, Intravenous
• Isoproterenol (pharmacology)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, cerebrospinal fluid)
• Male
• Oligopeptides (administration & dosage, pharmacology)
• Phosphorylation
• Pia Mater (blood supply)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• Swine
• Time Factors
• Up-Regulation
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, cerebrospinal fluid)