Molecular physiology of preconditioning-induced brain tolerance to ischemia

Ischemic tolerance describes the adaptive biological response of cells and organs that is initiated by preconditioning (i.e., exposure to stressor of mild severity) and the associated period during which their resistance to ischemia is markedly increased. This topic is attracting much attention because preconditioning-induced ischemic tolerance is an effective experimental probe to understand how the brain protects itself. This review is focused on the molecular and related functional changes that are associated with, and may contribute to, brain ischemic tolerance. When the tolerant brain is subjected to ischemia, the resulting insult severity (i.e., residual blood flow, disruption of cellular transmembrane gradients) appears to be the same as in the naive brain, but the ensuing lesion is substantially reduced. This suggests that the adaptive changes in the tolerant brain may be primarily directed against postischemic and delayed processes that contribute to ischemic damage, but adaptive changes that are beneficial during the subsequent test insult cannot be ruled out. It has become clear that multiple effectors contribute to ischemic tolerance, including: 1) activation of fundamental cellular defense mechanisms such as antioxidant systems, heat shock proteins, and cell death/survival determinants; 2) responses at tissue level, especially reduced inflammatory responsiveness; and 3) a shift of the neuronal excitatory/inhibitory balance toward inhibition. Accordingly, an improved knowledge of preconditioning/ischemic tolerance should help us to identify neuroprotective strategies that are similar in nature to combination therapy, hence potentially capable of suppressing the multiple, parallel pathophysiological events that cause ischemic brain damage.