Transient cerebral ischemia (TCI) leads to the “delayed neuronal death” in selectively vulnerable brain areas including the CA1 area of the hippocampus. Kitagawa et al. firstly introduced ischemic preconditioning (IPC) as a strategy for attenuating ischemia-reperfusion injury in the brain using a gerbil model of TCI2, and further studies have widely demonstrated IPC in other animal models of transient focal cerebral ischemia. This phenomenon is called cerebral “ischemic tolerance”, although basic mechanisms of underlying cerebral ischemic tolerance have not been fully understood yet.
Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine cyclin-dependent kinase family member, plays crucial roles in neuronal differentiation, axonal outgrowth, synaptogenesis and memory formation. The activation of Cdk5 leads to the translocation of Cdk5 from membrane to cytoplasm or nucleus. Studies using rodents have also demonstrated that the aberrant activity of Cdk5 primarily induces neuronal cell death during stroke. 
p53 (a tumor suppressor) displays important roles in regulating neuronal survival in the central nervous system. However, whether this process occurs in IPC-induced neurons suffering from a subsequent TCI is not clear; variously possible explanations of neuroprotective effects of IPC against a subsequent ischemic damage are proposed.

Down-regulation of Cdk5 by ischemic preconditioning attenuates p53-dependent apoptosis of hippocampal CA1 neurons following a subsequent transient cerebral ischemia