title: Postischemic oxidative stress promotes mitochondrial metabolic failure in neurons and astrocytes.
abstract: Oxidative stress and mitochondrial dysfunction have been closely associated in many subcellular, cellular, animal, and human studies of both acute brain injury and neurodegenerative diseases. Our animal models of brain injury caused by cardiac arrest illustrate this relationship and demonstrate that both oxidative molecular modifications and mitochondrial metabolic impairment are exacerbated by reoxygenation of the brain using 100% ventilatory O(2) compared to lower levels that maintain normoxemia. Numerous molecular mechanisms may be responsible for mitochondrial dysfunction caused by oxidative stress, including oxidation and inactivation of mitochondrial proteins, promotion of the mitochondrial membrane permeability transition, and consumption of metabolic cofactors and intermediates, for example, NAD(H). Moreover, the relative contribution of these mechanisms to cell injury and death is likely different among different types of brain cells, for example, neurons and astrocytes. In order to better understand these oxidative stress mechanisms and their relevance to neurologic disorders, we have undertaken studies with primary cultures of astrocytes and neurons exposed to O(2) and glucose deprivation and reoxygenation and compared the results of these studies to those using a rat model of neonatal asphyxic brain injury. These results support the hypothesis that release and or consumption of mitochondrial NAD(H) is at least partially responsible for respiratory inhibition, particularly in neurons.
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. gfiskum@anes.umm.edu
authors.forename: Gary
authors.initials: G
authors.lastname: Fiskum
authors.forename: Camelia A
authors.initials: CA
authors.lastname: Danilov
authors.forename: Zara
authors.initials: Z
authors.lastname: Mehrabian
authors.forename: Linda L
authors.initials: LL
authors.lastname: Bambrick
authors.forename: Tibor
authors.initials: T
authors.lastname: Kristian
authors.forename: Mary C
authors.initials: MC
authors.lastname: McKenna
authors.forename: Irene
authors.initials: I
authors.lastname: Hopkins
authors.forename: E M
authors.initials: EM
authors.lastname: Richards
authors.forename: Robert E
authors.initials: RE
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress