Respiratory Chain Inhibition Induces Tolerance to Focal Cerebral Ischemia

Journal of Cerebral Blood Flow and Metabolism - Tập 19 Số 11 - Trang 1229-1237 - 1999
Frank Wiegand1, Weijing Liao2, Christina Busch2, Sofía Daiana Castell2, F.F. Knapp2, Ute Lindauer2, Dirk Megow2, Andreas Meisel2, A. Redetzky2, Karsten Ruscher2, Abass Eidizadeh2, I. V. Victorov2, Matthias W. Riepe1, H C Diener1, Ulrich Dirnagl2
1Department of Neurology, Essen University, Essen
2Department of Neurology, Humboldt University, Berlin; and † Department of Neurology, University of Ulm, Ulm, Germany

Tóm tắt

The authors show that the inhibitor of the succinate dehydrogenase, 3-nitroproprionic acid (3-NPA), which in high doses and with chronic administration is a neurotoxin, can induce profound tolerance to focal cerebral ischemia in the rat when administered in a single dose (20 mg/kg) 3 days before ischemia. Infarcts were approximately 70% and 35% smaller in the 3-NPA preconditioned groups of permanent and transient focal cerebral ischemia, respectively. This regimen of 3-NPA preconditioning neither induced necrosis, apoptosis, or any other histologically detectable damage to the brain, nor did it affect behavior of the animals. 3-NPA led to an immediate (1-hour) and long-lasting (3-day) decrease in succinate dehydrogenase activity (30% reduction) throughout the brain, whereas only a short metabolic impairment occurred (ATP decrease of 35% within 30 minutes, recovery within 2 hours). The authors found that 3-NPA induces a burst of reactive oxygen species and the free radical scavenger dimethylthiourea, when administered shortly before the 3-NPA stimulus, completely blocked preconditioning. Inhibition of protein synthesis with cycloheximide given at the time of 3-NPA administration completely inhibited preconditioning. The authors were unsuccessful in showing upregulation of mRNA for the manganese superoxide dismutase, and did not detect increased activities of the copper-zinc and manganese superoxide dismutases, prototypical oxygen free radicals scavenging enzymes, after 3-NPA preconditioning. The authors conclude that it is possible to pharmacologically precondition the brain against focal cerebral ischemia, a strategy that may in principal have clinical relevance. The data show the relevance of protein synthesis for tolerance, and suggests that oxygen free radicals may be critical signals in preconditioning.

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Thông tin xuất bản

Journal of Cerebral Blood Flow and Metabolism

Tập 19 Số 11

1229-1237

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