Ischemic tolerance in the brain: Endogenous adaptive machinery against ischemic stress

Although more than 100 drugs have been examined clinically, tissue plasminogen activator remains the only drug approved for the treatment of acute ischemic stroke. Since the discovery of ischemic tolerance, it has been widely recognized that the brain possesses an endogenous protective machinery to protect against ischemic stress. Recent studies have clarified that both the upregulation of neuroprotective signaling and the downregulation of inflammatory or apoptotic pathways are involved equally in the acquisition of ischemic tolerance. The triggering stimuli for ischemic stresses are divided into hypoxic, oxidant/inflammatory, and glutamate stress. Glutamate stress, particularly the synaptic stimulation of the N-methyl-D-aspartate receptor, leads to activation of the cAMP response element-binding protein, which could subsequently induce gene expression of several neuroprotective molecules. Gene reprogramming and metabolic downregulation are intimately involved in ischemic tolerance as well as in hibernation and hypothermia. Micro-RNAs may be a key player for tuning the level of gene expression in ischemic tolerance. Future research should be performed to investigate the most effective combination for brain protection, enhancement of cell survival signaling, and inhibition of the inflammatory or apoptotic pathways.