Transient Neuronal Depolarization Induces Tolerance to Subsequent Forebrain Ischemia in Rats

Background: Minor cortical injury has previously been shown to improve survival in animals subjected to ischemic insults. Although the mechanism by which an ischemia-tolerant state is achieved is not clear, transient neuronal depolarization is thought to play a central role in the development of the tolerance. One way of producing transient neuronal depolarization is by the induction of cortical spreading depression (CSD). The present study was conducted to evaluate the effect of preischemic transient depolarization, induced by CSD, on postischemic neuronal outcome in rats.

Methods: Unilateral CSD was induced by application of KCl to the frontal cortex (CSD hemisphere) in three groups of isoflurane-anesthetized rats (CSD groups; n = 8/group). Sham animals (n = 12) did not undergo CSD. In a fifth group (n = 8), ketamine was administered during KCl application to inhibit CSD. One, three, or seven days after CSD, animals were subjected to forebrain ischemia produced by bilateral carotid artery occlusion. Injury to the striatum, hippocampus, and cortex was evaluated in hematoxylin and eosin-stained brain sections 3 days after ischemia.

Results: Preischemic CSD reduced postischemic injury in the ipsilateral cortex. The ratio of the number of injured neurons in the CSD hemisphere to that in the non-CSD hemisphere was significantly less in the groups subjected to CSD 1 day (0.51 +/- 0.33), 3 days (0.56 +/- 0.22), and 7 days (0.40 +/- 0.17) before ischemia than in the sham operated group (1.11 +/- 0.47). In the ketamine group (CSD inhibition), there were no differences in the extent of injury in the two hemispheres (ratio = 0.84 +/- 0.47). Injury to the striatum and hippocampus was similar among the groups. Within each group, injury to these subcortical structures in the CSD hemisphere was not different from that in the non-CSD hemisphere.