Cerebroprotective effects of the CO-releasing molecule CORM-A1 against seizure-induced neonatal vascular injury.
Endogenous CO, a product of heme oxygenase activity, has vasodilator and cytoprotective effects in the cerebral circulation of newborn pigs. CO-releasing molecule (CORM)-A1 (sodium boranocarbonate) is a novel, water-soluble, CO-releasing compound. We addressed the hypotheses that CORM-A1 1) can deliver CO to the brain and exert effects of CO on the cerebral microvasculature and 2) is cerebroprotective. Acute and delayed effects of topically and systemically administered CORM-A1 on cerebrovascular and systemic circulatory parameters were determined in anesthetized newborn pigs with implanted closed cranial windows. Topical application of CORM-A1 (10(-7)-10(-5) M) to the brain produced concentration-dependent CO release and pial arteriolar dilation. Systemically administered CORM-A1 (2 mg/kg ip or iv) caused pial arteriolar dilation and increased cortical cerebrospinal fluid CO concentration. Systemic CORM-A1 did not have acute or delayed effects on blood pressure, heart rate, or blood gases. Potential cerebroprotective vascular effects of CORM-A1 (2 mg/kg ip, 30 min before seizures) were tested 2 days after bicuculline-induced epileptic seizures (late postictal period). In control piglets, seizures reduced postictal cerebrovascular responsiveness to selective physiologically relevant vasodilators (bradykinin, hemin, and isoproterenol) indicative of cerebrovascular injury. In contrast, in CORM-A1-pretreated animals, no loss of postictal cerebrovascular reactivity was observed. We conclude that systemically administered CORM-A1 delivers CO to the brain, elicits the vasodilator and cytoprotective effects of CO in the cerebral circulation, and protects the neonatal brain from cerebrovascular injury caused by epileptic seizures.
Zimmermann
Aliz
A
Laboratory for Research in Neonatal Physiology, Department of Physiology, Vascular Biology Center, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Leffler
Charles W
CW
Tcheranova
Dilyara
D
Fedinec
Alexander L
AL
Parfenova
Helena
H
D000287:Administration, Topical; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline; D001794:Blood Pressure / Q000187:drug effects; D001880:Boranes / Q000494:pharmacology* / Q000627:therapeutic use; D001920:Bradykinin / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D002254:Carbonates / Q000494:pharmacology* / Q000627:therapeutic use; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006427:Hemin / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007545:Isoproterenol / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D001880:Boranes; D002254:Carbonates; D020011:Protective Agents; D014665:Vasodilator Agents; C503854:sodium boranocarbonate; D009599:Nitroprusside; D006427:Hemin; D002248:Carbon Monoxide; D007545:Isoproterenol; D001920:Bradykinin; D001640:Bicuculline