title: Antioxidant roles of heme oxygenase, carbon monoxide, and bilirubin in cerebral circulation during seizures.
abstract: Postictal cerebrovascular dysfunction is an adverse effect of seizures in newborn piglets. The brain heme oxygenase (HO) provides protection against cerebrovascular dysfunction. We investigated the contribution of reactive oxygen species (ROS) to seizure-induced vascular damage and the mechanism of HO vasoprotection. In a bicuculline model of seizures, we addressed the hypotheses: (1) seizures increase brain ROS; (2) ROS contribute to cerebral vascular dysfunction; (3) ROS initiate a vasoprotective mechanisms by activating endogenous HO; and (4) HO products have antioxidant properties. As assessed by dihydroethidium oxidation (ox-DHE), seizures increased ROS in cerebral vessels and cortical astrocytes; ox-DHE elevation was prevented by tiron and apocynin. An HO inhibitor, tin protoporphyrin, potentiated, whereas an HO-1 inducer, cobalt protoporphyrin, blocked seizure-induced increase in DHE oxidation. Heme oxygenase products carbon monoxide (CO) (CORM-A1) and bilirubin attenuated ox-DHE elevation during seizures. Antioxidants tiron and bilirubin prevented the loss of postictal cerebrovascular dilations to bradykinin, glutamate, and sodium nitroprusside. Tiron and apocynin abrogated activation of the brain HO during seizures. Overall, these data suggest that long-term adverse cerebrovascular effects of seizures are attributed to oxidative stress. On the other hand, seizure-induced ROS are required for activation of the endogenous antioxidant HO/CO/bilirubin system that alleviates oxidative stress-induced loss of postictal cerebrovascular function in piglets.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA. hparfeno@uthsc.edu
authors.forename: Helena
authors.initials: H
authors.lastname: Parfenova
authors.forename: Charles W
authors.initials: CW
authors.lastname: Leffler
authors.forename: Shyamali
authors.initials: S
authors.lastname: Basuroy
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Liu
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Fedinec
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism*; D001920:Bradykinin / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D008665:Metalloporphyrins / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012640:Seizures / Q000378:metabolism* / Q000503:physiopathology; D013552:Swine
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D009419:Nerve Tissue Proteins; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin; D001920:Bradykinin