Respiratory chain inhibition induces tolerance to focal cerebral ischemia.
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.
Wiegand
F
F
Department of Neurology, Essen University, Germany.
Liao
W
W
Busch
C
C
Castell
S
S
Knapp
F
F
Lindauer
U
U
Megow
D
D
Meisel
A
A
Redetzky
A
A
Ruscher
K
K
Trendelenburg
G
G
Victorov
I
I
Riepe
M
M
Diener
H C
HC
Dirnagl
U
U
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D003292:Convulsants / Q000008:administration & dosage*; D005609:Free Radicals; D019194:Ischemic Preconditioning; D008297:Male; D009574:Nitro Compounds; D011422:Propionates / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*
D003292:Convulsants; D005609:Free Radicals; D009574:Nitro Compounds; D011422:Propionates; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid