Heme oxygenase and cerebral vascular injury

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

DESCRIPTION (provided by applicant): Mechanisms by which seizures affect cerebral circulation in newborns are of physiological and potentially clinical importance. Carbon monoxide (CO) and biliverdin/bilirubin formed in the brain from intracellular heme I via the heme oxygenase (HO) pathway are a vasodilator and antioxidants, respectively. My published and preliminary data suggest: 1) seizures dilate cerebral arterioles and increase cerebral blood flow, 2) seizures cause activation of HO in the brain, 3) HO inhibition attenuates cerebral dilation to seizures and results in sustained postictal cerebral vascular dysfunction, 4) HO upregulation may prevent postictal cerebral vascular dysfunction, 5) the seizure-associated excitotoxic neuromediator, glutamate, dilates cerebral arterioles and increases cerebral vascular HO activity, 6) glutamate receptors are detected in cerebral microvascular endothelial cells (CMVEC). The research proposed will pursue the hypothesis that heme oxygenase provides endogenous vascular protection against seizure-induced postictal vascular dysfunction in the neonatal cerebral circulation. Three specific aims will be addressed using in vivo and in vitro techniques in newborn pigs. SPECIFIC AIM 1. Evaluate, in vivo, the relationship between activation of HO and cerebrovascular dysfunction secondary to glutamatergic seizures. SPECIFIC AIM 2. Examine the mechanism(s) by which HO diminishes postictal cerebrovascular dysfunction. SPECIFIC AIM 3. To explore a potential mechanism by which glutamate increases the protective HO activity, test, in vitro, the hypothesis that cerebral microvessels express glutamate receptors (GluRs) that are functionally linked to HO. I will use in vivo and in vitro techniques to investigate intact cerebral microcirculation, isolated cerebral arterioles, and CMVEC. Cranial window techniques allow investigation of cerebral circulation in vivo. Intact and endothelium-denuded isolated pressurized cerebral arterioles will be used to examine vascular responses to glutamate in situ. CMVEC in primary cultures in vitro will be studied to uncover the cellular and molecular mechanisms by which glutamate stimulates HO activity. Seizures in newborn children are frequently associated with long-lasting neurological disabilities and increase chances of subsequent development of chronic epilepsy. Better understanding of the mechanisms of postictal cerebral vascular dysfunction is needed to improve the long-term neurological outcome in human newborns.