Protective Preconditioning by Transient Global Ischemia in the Rat: Components of Delayed Injury Progression and Lasting Protection Distinguished by Comparisons of Depolarization Thresholds for Cell Loss at Long Survival Times

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Abstract
Robust ischemic preconditioning has been shown in rodent brain, but there are concerns regarding the persistence of neuron protection. This issue was examined in rat hippocampus following 4-vessel occlusion (4-VO) ischemia, using DC shifts characteristic of ischemic depolarization to reproducibly define insult severity. Preconditioning ischemia producing 2 to 3.5 mins depolarization was followed at intervals of 2, 5, or 7 days by test insults of varied duration, after which CA1 counts were obtained at 1, 2, 4, or 12 weeks. Neuron loss in naive animals increased with depolarization time longer than 4 mins regardless of postischemic survival interval. Preconditioning 2, 5, or 7 days before test insults prolonged the injury threshold evaluated at 1 week survival to 15, 9, or 6 mins, respectively, showing robust protection and a rapid decay of the protected state. However, by 2 weeks survival after preconditioning at a 2-day interval, the injury threshold dramatically regressed from 15 to 9 mins. Thereafter protection remained relatively stable through 1 month, but slight progression of neuron injury was evident at 3 months. Inflammatory responses were seen in both naive and preconditioned hippocampi throughout this interval, appropriate to the extent of neuron injury. These studies show distinct components of transient and lasting protection after ischemic preconditioning. Finally, it was found that ischemic depolarization was delayed by approximately 1 min in optimally preconditioned rat hippocampus, in contrast to previous results in the gerbil, identifying one specific mechanism by which insult severity is reduced in this model.

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