Respiratory Chain Inhibition Induces Tolerance to Focal Cerebral Ischemia

Abstract

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.

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

“…This approach has already been demonstrated to be beneficial in case of 3-NP: the low-dose of toxin treatment increased the tolerance to ischemia and hypoxia in rats and gerbils (Horiguchi et al, 2003;Riepe et al, 1997;Wiegand et al, 1999). Although the exact mechanism in the background is not fully understood, the overexpression of free radical scavenging enzymes may be involved: acute 3-NP treatment activated superoxide dismutase (SOD) and catalase (CAT) in several brain areas (Binienda et al, 1998).…”

The neuroprotective mechanism of brain ischemic preconditioning

“…However, recent studies [5,78] indicate that oxygen free radicals also have an important role in triggering the signal transduction pathways in ischemic preconditioning. Some oxygen free radicals such as hydroxyl radicals (· OH) may be involved in ischemic preconditioning induction [79] .…”

“…This observation suggests that ischemic preconditioning is an adaptive reaction to a potentially noxious stimulus, such as ischemia, hypoxia, hypoglycemia, or inflammation. Although tolerance to ischemic insults can also result from cortical spreading depression [2] , sleep deprivation [3] , dietary restriction [4] , metabolic inhibition and oxygen free radicals [5] , and both hyperthermia and hypothermia [1] , ischemic preconditioning has been more aggressively studied.…”

3-Nitropropionic Acid-Induced Ischemia Tolerance in the Rat Brain is Mediated by Reduced Metabolic Activity and Cerebral Blood Flow

“…Interestingly, although the inhibition of succinate dehydrogenase after NPA application is immediate (30 minutes) and longer lasting (3 days), the direct effect of NPA on ATP synthesis is much shorter lasting (approximately 2 hours). 11 Histologic analysis proved the NPA-induced tissue protection suggested from MRI, however, selective neuronal death occurred in parts of the ischemic territory that were not detected on T2w MRI. This finding points out the importance of multimodal (imaging/functional testing/histology) readouts in the assessment of ischemic damage.…”