Ischemic Tolerance: The Mechanisms of Neuroprotective Strategy

Abstract

The phenomenon of ischemic tolerance perfectly describes this quote ''What does not kill you makes you stronger.'' Ischemic pre-or postconditioning is actually the strongest known procedure to prevent or reverse neurodegeneration. It works specifically in sensitive vulnerable neuronal populations, which are represented by pyramidal neurons in the hippocampal CA1 region. However, tolerance is effective in other brain cell populations as well. Although, its nomenclature is ''ischemic'' tolerance, the tolerant phenotype can also be induced by other stimuli that lead to delayed neuronal death (intoxication). Moreover, the recent data have proven that this phenomenon is not limited to application of sublethal stimuli before the lethal stress but reversed arrangement of events, sublethal stress after lethal insult, is rather equally effective. A very important term is called ''cross conditioning.'' Cross conditioning is the capability of one stressor to induce tolerance against another. So, since pre-or postconditioners can be used plenty of harmful stimuli, hypo-or hyperthermia and some physiological compounds, such as norepinephrine, bradykinin. Delayed neuronal death is the slow development of postischemic neurodegeneration. This allows an opportunity for a great therapeutic window of 2-3 days to reverse the cellular death process. Moreover, it seems that the mechanisms of ischemic tolerance-delayed postconditioning could be used not only after ischemia but also in some other processes leading to apoptosis.

Ischemic preconditioning maintains immunoreactivities of glucokinase and glucokinase regulatory protein in neurons of the gerbil hippocampal CA1 region following transient cerebral ischemia

“…The concept of IPC is defined as a brief, non-injurious episode of ischemia, which can protect the brain cells from a subsequent longer ischemic insult (10,11). The first description of IPC in the brain was reported in a study by Kitagawa et al (30) in a gerbil model of global ischemia.…”

“…However, the exact mechanisms underlying neuronal damage in ischemia and delayed neuronal death remain to be fully elucidated. Ischemic preconditioning (IPC) represents an important adaptation of the central nervous system to sub-lethal ischemia, which results in an increased tolerance to ischemia in the central nervous system to a subsequent longer or lethal period of ischemia (10,11). IPC induces the expression of a diverse family of genes involved in cytoprotection, which, in turn, encode proteins that enhance brain resistance to ischemia (12).…”

Mechanisms of Ischemic Induced Neuronal Death and Ischemic Tolerance

“…A series of papers (Urban et al, 2009;Lehotsky et al, 2009b;Pavlikova et al,2009) found that ischemia/reperfusion injury (IRI) initiates time dependent differences in endoplasmic reticular gene expression at both the mRNA and protein levels in rat hippocampus and that endoplasmic gene expression is affected by pre-ischemic treatment. More recently, Pavlikova et al (2011) conducted an investigation into the differences between naive control and hyperhomocysteinemic control animals in each group independently.…”

“…This leads to the trigger of the neuroprotective tolerance state. A number of common mechanisms with different relevance features can be recognized (Lehotsky et al, 2009b): -depression of metabolic rate, -modulation of glycolytic enzymes, -reduction of ion channel fluxes, -suppression of neural activity, -expression of chaperones and heat shock proteins (Hsp), -activation of antioxidant defense systems, -adaptation of blood rheology and others. At first pass, the patient population that suffers from cerebral ischemic injury due to unpredictable focal stroke, cardiac arrest, or subarachnoid hemorrhage represents, by definition, one that is unlikely to derive benefit from preconditioning research.…”

“…Temporary defined responses during therapeutical window may induce protective response with which subsequent ischemia serve as basis of the ischemic-tolerant phenotype. Adapted from Lehotsky et al (2009b).…”