1. ^*Sanders-Brown Research Center on Aging, Wayne State University, Detroit, Michigan, U.S.A.
2. ^†Department of Biochemistry, University of Kentucky, Detroit, Michigan, U.S.A.
3. ^‡Veterans Affairs Medical Center, University of Kentucky, Lexington, KY 40536-0230, U.S.A.
4. ^§Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan, U.S.A.

Correspondence: Jeffrey N. Keller, 101 Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, U.S.A.

Received 20 April 2000; Revised 8 June 2000; Accepted 12 June 2000.

Abstract

Numerous studies indicate a role for oxidative stress in the neuronal degeneration and cell death that occur during ischemia–reperfusion injury. Recent data suggest that inhibition of the proteasome may be a means by which oxidative stress mediates neuronal cell death. In the current study, the authors demonstrate that there is a time-dependent decrease in proteasome activity, which is not associated with decreased expression of proteasome subunits, after cerebral ischemia–reperfusion injury. To determine the role of oxidative stress in mediating proteasome inhibition, ischemia–reperfusion studies were conducted in mice that either overexpressed the antioxidant enzyme glutathione peroxidase [GPX 1(+)], or were devoid of glutathione peroxidase activity (GPX -/-). After ischemia–reperfusion, GPX 1(+) mice displayed decreased infarct size, attenuated neurologic impairment, and reduced levels of proteasome inhibition compared with either GPX -/- or wild type mice. In addition, GPX 1(+) mice displayed lower levels of 4-hydroxynonenal-modified proteasome subunits after ischemia–reperfusion injury. Together, these data indicate that proteasome inhibition occurs during cerebral ischemia–reperfusion injury and is mediated, at least in part, by oxidative stress.