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.

Cerebral Ischemic Preconditioning: the Road So Far…

“…Formed normally through changes in posttranslational modifications, the window of protection is very small and recedes after a few hours. Delayed or classical preconditioning prevails due to genetic alterations and protein synthesis and hence is of more significance within the ischemic region [11,12]. It is longer in duration, from a few hours to several days but usually less than a week.…”

“…It is longer in duration, from a few hours to several days but usually less than a week. Between the early and delayed IT, there is usually an unprotected window with little or no tolerance [11]. These two phases of IT brought about by preconditioning possibly work by diverse mechanisms and in varied time frames in different tissues of the brain [12].…”

“…These two phases of IT brought about by preconditioning possibly work by diverse mechanisms and in varied time frames in different tissues of the brain [12]. Factors that may affect the scope of CPC include age, gender, and strain of the animals used as models for cerebral ischemia [11,13].…”

The Protective Effect of Remote Renal Preconditioning Against Hippocampal Ischemia Reperfusion Injury: Role of KATP Channels

“…Therefore, researchers turned to the endogenous mechanisms in order to enable the brain to increase its tolerance against the lethal and prolonged ischemia (Bhuiyan and Kim 2010;Durukan and Tatlisumak 2010). One of these known mechanisms is ischemia preconditioning (IPC), which is known as a natural adaptive process that activates multiple cellular signaling pathways.…”

Effects of Limb Remote Postconditioning on Apoptosis and Long-Term Neurological Outcomes of Focal Cerebral Ischemia/Reperfusion Injury in Rats

“…Therefore, innovative treatment strategies for protecting brain against the detrimental effects of this form of injury are required in order to improve clinical outcomes in patients with brain ischemic injury. Researchers are now interested in the brain's endogenous strategies for neuroprotection [6,7]. Harnessing the endogenous protection elicited by the brain's ability to "condition" itself has recently emerged as a powerful new strategy for limiting brain injury [8,9].…”