Abstract: Cortical spreading depression is a technique used to depolarize neurons. During focal or global ischemia, cortical spreading depression-induced preconditioning can enhance tolerance of further injury. However, the underlying mechanism for this phenomenon remains relatively unclear. To date, numerous issues exist regarding the experimental model used to precondition the brain with cortical spreading depression, such as the administration route, concentration of potassium chloride, induction time, duration of the protection provided by the treatment, the regional distribution of the protective effect, and the types of neurons responsible for the greater tolerance. In this review, we focus on the mechanisms underlying cortical spreading depression-induced tolerance in the brain, considering excitatory neurotransmission and metabolism, nitric oxide, genomic reprogramming, in?ammation, neurotropic factors, and cellular stress response. Specifcally, we clarify the procedures and detailed information regarding cortical spreading depression-induced preconditioning and build a foundation for more comprehensive investigations in the feld of neural regeneration and clinical application in the future.

Key words: nerve regeneration, cortical spreading depression, neuronal depolarization, ischemic tolerance, peri-infarct depolarization, excitatory neurotransmission, nitric oxide, genomic reprogramming, in?ammation, neurotropic factors, cellular stress response, neural regeneration