Cerebroprotective effects of the CO-releasing molecule CORM-A1 against seizure-induced neonatal vascular injury

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 293; no. 4; p. H2501
• Main Authors: Zimmermann, Aliz, Leffler, Charles W, Tcheranova, Dilyara, Fedinec, Alexander L, Parfenova, Helena
• Format: Journal Article
• Language: English
• Published: United States 01-10-2007
• Subjects: Administration, Topical; Animals; Animals, Newborn; Bicuculline; Blood Pressure - drug effects; Boranes - pharmacology; Boranes - therapeutic use; Bradykinin - metabolism; Carbon Monoxide - metabolism; Carbonates - pharmacology; Carbonates - therapeutic use; Cerebral Arteries - drug effects; Cerebral Arteries - metabolism; Cerebral Arteries - physiopathology; Cerebrovascular Circulation - drug effects; Cerebrovascular Disorders - etiology; Cerebrovascular Disorders - metabolism; Cerebrovascular Disorders - physiopathology; Cerebrovascular Disorders - prevention & control; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate - drug effects; Hemin - pharmacology; Injections, Intraperitoneal; Injections, Intravenous; Isoproterenol - pharmacology; Nitroprusside - pharmacology; Protective Agents - administration & dosage; Protective Agents - pharmacology; Protective Agents - therapeutic use; Seizures - chemically induced; Seizures - complications; Seizures - metabolism; Seizures - physiopathology; Swine; Vasodilation - drug effects; Vasodilator Agents - administration & dosage; Vasodilator Agents - metabolism; Vasodilator Agents - pharmacology; Vasodilator Agents - therapeutic use
• ISSN: 0363-6135
• DOI: 10.1152/ajpheart.00354.2007

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.