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The Journal of Neuroscience, September 1, 2001, 21(17):6608-6616

The Mitochondrial Permeability Transition Pore and Nitric Oxide Synthase Mediate Early Mitochondrial Depolarization in Astrocytes during Oxygen-Glucose Deprivation

Susan A. Reichert, Jeong Sook Kim-Han, and Laura L. Dugan

Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110

Recent studies suggest that the degree of mitochondrial dysfunction in cerebral ischemia may be an important determinant of the final extent of tissue injury. Although loss of mitochondrial membrane potential (_m), one index of mitochondrial dysfunction, has been documented in neurons exposed to ischemic conditions, it is not yet known whether astrocytes, which are relatively resistant to ischemic injury, experience changes in _m under similar conditions. To address this, we exposed cortical astrocytes cultured alone or with neurons to oxygen-glucose deprivation (OGD) and monitored _m using tetramethylrhodamine ethyl ester. Both neurons and astrocytes exhibited profound loss of _m after 45-60 min of OGD. However, although this exposure is lethal to nearly all neurons, it is hours less than that needed to kill astrocytes. Astrocyte _m was rescued during OGD by cyclosporin A, a permeability transition pore blocker, and ^GN-nitro-arginine, a nitric oxide synthase inhibitor. Loss of mitochondrial membrane potential in astrocytes was not accompanied by depolarization of the plasma membrane. Recovery of astrocyte _m after reintroduction of O₂ and glucose occurred over a surprisingly long period (>1 hr), suggesting that OGD caused specific, reversible changes in astrocyte mitochondrial physiology beyond the simple lack of O₂ and glucose. Decreased _m was associated with a cyclosporin A-sensitive loss of cytochrome c but not with activation of caspase-3 or caspase-9. Our data suggest that astrocyte mitochondrial depolarization could be a previously unrecognized event early in ischemia and that strategies that target the mitochondrial component of ischemic injury may benefit astrocytes as well as neurons.

Key words: tetramethylrhodamine ethyl ester; mitochondrial permeability transition pore; nitric oxide synthase; cyclosporin A; confocal microscopy; cortical cell cultures

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21176608-09$05.00/0

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