Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Abstract

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells.

Figure 1

Outcomes in the different settings with middle cerebral artery occlusion (MCAO). In the absence of ischemic preconditioning (IPC), MCAO induces a large infarction (ischemia-sensitive phenotype). IPC results early ischemic tolerance (IT) in minutes; if MCAO is applied during this phase, mainly cortical areas are spared (early ischemia-tolerant phenotype). In hours, the brain regresses to its naïve state. Delayed phase of IT occurs in days, when the latent cerebroprotective phenotype is complete, the brain is again ischemia-tolerant.

Figure 2

Exemplary protocol of a series of ischemic tolerance (IT) experiments. Preconditioning ischemia (IPC) lasts 5 min, final ischemia 10 min. Cross indicates the end of the study where the brains are collected for ex vivo evaluations. Set I experiments evaluate early IT: final ischemia is applied 30 min after IPC (upper row), early ischemia-tolerant phenotype is tested by collecting the brains 25 min after PC, and in the control experiment, final ischemia is induced without prior IPC (lower row). In Set II experiments, delayed IT (upper row, final ischemia induction 24 h after the PC) and delayed ischemia-tolerant phenotype (middle row, brains are collected 24 h after PC) are investigated, along with a control experiment (lower row). Set III experiments address long-lasting effects of delayed-IT, with a follow-up lasting several weeks after final ischemia.