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 mecha nism by which an ischemia-tolerant state is achieved is not clear, tra nsient neuronal depolarization is thought to play a central role in th e development of the tolerance. One way of producing transient neurona l depolarization is by the induction of cortical spreading depression (CSD). The present study was conducted to evaluate the effect of preis chemic transient depolarization, induced by CSD, on postischemic neuro nal outcome in rats. Methods: Unilateral CSD was induced by applicatio n of KCl to the frontal cortex (CSD hemisphere) in three groups of iso flurane-anesthetized rats (CSD groups; n = 8/group). Sham animals (n = 12) did not undergo CSD. In a fifth group (n = 8), ketamine was admin istered during KCl application to inhibit CSD. One, three, or seven da ys after CSD, animals were subjected to forebrain ischemia produced by bilateral carotid artery occlusion. Injury to the striatum, hippocamp us, and cortex was evaluated in hematoxylin and eosin-stained brain se ctions 3 days after ischemia. Results: Preischemic CSD reduced postisc hemic injury in the ipsilateral cortex. The ratio of the number of inj ured neurons in the CSD hemisphere to that in the non-CSD hemisphere w as 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 ischem ia than in the sham operated group (1.11 +/- 0.47). In the ketamine gr oup (CSD inhibition), there were no differences in the extent of injur y in the two hemispheres (ratio = 0.84 +/- 0.47). Injury to the striat um and hippocampus was similar among the groups. Within each group, in jury to these subcortical structures in the CSD hemisphere was not dif ferent from that in the non-CSD hemisphere. Conclusions: The data sugg est that preischemic depolarization induced by CSD results in an adapt ive response that reduces the vulnerability of cortical neurons to sub sequent ischemic injury (ischemic tolerance).