Mechanisms of Ischemic Induced Neuronal Death and Ischemic Tolerance

Abstract

Stroke is the second leading cause of death and the primary cause of disability in humans. The phenomenon of ischemic tolerance perfectly describes the quote: “What does not kill you makes you stronger.’’ Ischemic preor postconditioning is actually the strongest known procedure to prevent or reverse delayed neuronal death. 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 (IT) ”, the tolerant phenotype can also be induced by other stimuli that lead to delayed neuronal death (intoxication). Recent data have proven further that this phenomenon is not only limited to application of sublethal stimuli before the lethal stress (preconditioning) but also that reversed arrangement of events, sublethal stress after lethal insult (postconditioning), are equally effective. Another very important term is ‘‘cross conditioning,’’ or the capability of one stressor to induce tolerance against another. Delayed neuronal death is the slow development of post-ischemic neuro-degeneration. This delay allows a therapeutic window of opportunity lasting 2–3 days to reverse the cellular death process. It seems therefore that the mechanisms of ischemic tolerance-delayed post-conditioning could be of use not only after ischemia but also in some other processes leading up to apoptosis. This paper summarizes results of experimental studies which have shown that acute in vivo forebrain ischemia as well as ischemic/reperfusion injury (IRI) both alter, the expression, function and kinetic parameters of Ca2+ transporters as well as the physical membrane environment. Furthermore, that IRI leads to the inhibition of mitochondrial respiratory complexes I and IV. Also, that conversely, ischemic preconditioning (IPC) acts at the level of both initiation and execution of IRI-induced mitochondrial apoptosis and activates inhibition of p53 translocation to mitochondria. Evidence is presented to show that endoplasmic reticulum (ER) is the site of complex processes such as calcium storage, synthesis and folding of proteins as well as cell response to stress. ER function is impaired in IRI which in turn induces depletion of stored calcium, the conserved stress responses linked with delayed neuronal death. In addition, IRI initiates time dependent differences in endoplasmic reticular (ER) gene expression of the key