Antioxidant roles of heme oxygenase, carbon monoxide and bilirubin in cerebral circulation during epileptic seizures

Abstract

Epileptic seizures cause sustained loss of endothelium‐dependent regulation of cerebral blood flow. Heme oxygenase (HO) is cytoprotective against seizure‐induced cerebral endothelial dysfunction. Oxidative stress is a potential cause of vascular damage. Using a model of bicuculline‐induced epileptic seizures in newborn pigs, we addressed the hypotheses that: 1) seizures increase production of reactive oxygen species (ROS) in cerebral vasculature, 2) endogenous HO activity exerts antioxidant effects, and 3) CO and bilirubin exhibit antioxidant properties in cerebral circulation. As assessed by dihydroethidium (DHE) oxydation, seizures elevate ROS in cerebral vessels. Burst of ROS during seizures was blocked by tiron, a ROS scavenger, and reduced by apocynin, a NADPH oxidase inhibitor. A HO inhibitor, tin protoporphyrin, potentiated whereas a HO‐1 inducer, cobalt protoporphyrin, blocked the ROS increases in cerebral vessels during seizures. The products of HO activity, CO (as CORM‐A1, 2 mg/kg ip) and bilirubin (3–5 mg/kg, iv) administered before or during a 20‐min window after seizure onset attenuated ROS elevation. These data indicate that: 1) constitutive HO‐2 and inducible HO‐1 have antioxidant properties in cerebral vasculature; 2) antioxidant properties of CO and bilirubin could contribute to the HO‐mediated endothelial survival mechanism in cerebral circulation during epileptic seizures.