title: Enteral supplements of a carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by neonatal seizures.
abstract: Cerebral blood flow dysregulation caused by oxidative stress contributes to adverse neurologic outcome of seizures. A carbon monoxide (CO) donor CORM-A1 has antioxidant and cytoprotective properties. We investigated whether enteral supplements of CORM-A1 can improve cerebrovascular outcome of bicuculline-induced seizures in newborn piglets. CORM-A1 (2 mg/kg) was given to piglets via an oral gastric tube 10 minutes before or 20 minutes after seizure onset. Enteral CORM-A1 elevated CO in periarachnoid cerebrospinal fluid and produced a dilation of pial arterioles. Postictal cerebral vascular responses to endothelium-, astrocyte-, and vascular smooth muscle-dependent vasodilators were tested 48 hours after seizures by intravital microscopy. The postictal responses of pial arterioles to bradykinin, glutamate, the AMPA receptor agonist quisqualic acid, ADP, and heme were greatly reduced, suggesting that seizures cause injury to endothelial and astrocyte components of the neurovascular unit. In contrast, in the two groups of piglets receiving enteral CORM-A1, the postictal cerebral vascular responsiveness to these dilators was improved. Overall, enteral supplements of CORM-A1 before or during seizures offer a novel effective therapeutic option to deliver cytoprotective mediator CO to the brain, reduce injury to endothelial and astrocyte components of cerebral blood flow regulation and to improve the cerebrovascular outcome of neonatal seizures.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Fedinec
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Leffler
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Parfenova
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D001880:Boranes / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D002248:Carbon Monoxide; D002254:Carbonates / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D006418:Heme / Q000494:pharmacology; D008297:Male; D016318:Quisqualic Acid / Q000494:pharmacology; D012640:Seizures / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013552:Swine; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001880:Boranes; D002254:Carbonates; D018690:Excitatory Amino Acid Agonists; D014665:Vasodilator Agents; C503854:sodium boranocarbonate; D018698:Glutamic Acid; D006418:Heme; D000244:Adenosine Diphosphate; D002248:Carbon Monoxide; D016318:Quisqualic Acid; D001920:Bradykinin