Preconditioning Depresses Excitatory Cell Signaling Following the Second Ischemic Insult

Abstract

Ischemic tolerance was induced in the rat using the two-vessel occlusion model of cerebral ischemia. Three minutes of preconditioning ischemia with 2–3 days of interischemic interval protected the brain from a subsequent period of lethal ischemia of 10–15 min duration. Calcium-calmodulin protein kinase II (CaMKII) is translocated from its cytosolic form to the membrane-bound form during ischemia. In the CA1 region the translocated protein is bound to the membrane fraction for up to 24h during recovery, without replenishment in the cytosolic fraction. Preconditioning ischemia decreases and normalizes the membrane bound CaMKII levels after 24h of recovery. Tyrosine phosphorylation of the NMDA receptor (NR2A/B) subunit is enhanced during recovery following ischemia. In preconditioned brain the tyrosine phosphorylation is decreased and normalized by 24h of recovery. The NR2A/ B subunit levels are markedly diminished after 24h of recovery. We propose that during the preconditioning, protective factors (growth factors and cytokines) are induced in neurons and/or glia cells, which in turn stimulate intracellular neuroprotective mechanisms such as enhancers of proteins synthesis or bcl-2 expression, which in concert with processes activated by the second ischemic insult downregulate deleterious processes including those elevating intracellular calcium ion concentrations.