Respiratory chain inhibition induces tolerance to focal cerebral ischemia

The authors show that the inhibitor of the succinate dehydrogenase, 3-nitro proprionic acid (3-NPA), which in high doses and with chronic administratio n 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 isc hemia. Infarcts were approximately 70% and 35% smaller in the 3-NPA precond itioned groups of permanent and transient focal cerebral ischemia, respecti vely. This regimen of 3-NPA preconditioning neither induced necrosis, apopt osis, or any other histologically detectable damage to the brain, nor did i t affect behavior of the animals. 3-NPA led to an immediate (l-hour) and lo ng-lasting (3-day) decrease in succinate dehydrogenase activity (30% reduct ion) throughout the brain, whereas only a short metabolic impairment occurr ed (ATP decrease of 35% within 30 minutes, recovery within 2 hours). The au thors found that 3-NPA induces a burst of reactive oxygen species and the f ree radical scavenger dimethylthiourea, when administered shortly before th e 3-NPA stimulus, completely blocked preconditioning. inhibition of protein synthesis with cycloheximide given at the time of 3-NPA administration com pletely inhibited preconditioning. The authors were unsuccessful in showing upregulation of mRNA for the manganese superoxide dismutase, and did not d etect increased activities of the copper-zinc and manganese superoxide dism utases, prototypical oxygen free radicals scavenging enzymes, after 3-NPA p reconditioning. The authors conclude that it is possible to pharmacological ly precondition the brain against focal cerebral ischemia, a strategy that may in principal have clinical relevance. The data show the relevance of pr otein synthesis for tolerance, and suggests that oxygen free radicals may b e critical signals in preconditioning.