From rapid to delayed and remote postconditioning: the evolving concept of ischemic postconditioning in brain ischemia

Abstract

Ischemic postconditioning is a concept originally defined to contrast with that of ischemic preconditioning. While both preconditioning and postconditioning confer a neuroprotective effect on brain ischemia, preconditioning is a sublethal insult performed in advance of brain ischemia, and postconditioning, which conventionally refers to a series of brief occlusions and reperfusions of the blood vessels, is conducted after ischemia/reperfusion. In this article, we first briefly review the history of preconditioning, including the experimentation that initially uncovered its neuroprotective effects and later revealed its underlying mechanisms-of-action. We then discuss how preconditioning research evolved into that of postconditioning--a concept that now represents a broad range of stimuli or triggers, including delayed postconditioning, pharmacological postconditioning, remote postconditioning--and its underlying protective mechanisms involving the Akt, MAPK, PKC and K(ATP) channel cell-signaling pathways. Because the concept of postconditioning is so closely associated with that of preconditioning, and both share some common protective mechanisms, we also discuss whether a combination of preconditioning and postconditioning offers greater protection than preconditioning or postconditioning alone.

Fig. 1

Preconditioning and postconditioning time lines and their stimulus types. While preconditioning is conducted before ischemia onset, postconditioning is induced post ischemia/reperfusion. Both preconditioning and postconditioning can be performed with a number of stimuli, and consist of both rapid and delayed time windows.

Fig. 2

The cell signaling pathways involved in ischemic postconditioning. Reactive oxygen species (ROS) eruption after reperfusion causes dysfunction of the Akt cell signaling pathway, increases sσPKC activity while decreases εPKC activity. ROS also activates JNK and ERK activity. Furthermore, the PI3K/Akt inhibition directly results in dephosphorylation of GSK3β and Bad, and indirectly causes cytochrome c release from the mitochondria and caspases activity. Akt inhibition also results in activation of the transcription factor, FKHR (FOXO1), which increases Fas ligand and Bim expression. ROS, reactive oxygen species; Cyto C, cytochrome c; Cas-3, caspase-3; GSK 3 b, glycogen synthase kinase 3b; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; P-Akt, phosphorylated Akt; P-PTEN, phosphorylated phosphatase and tensin homolog deleted on chromosome 10; P-PDK1, phosphorylated phosphoinositide-dependent protein kinase-1; JNK, c-Jun N-terminal kinases; ERK, extracellular signal-regulated kinases; KATP channels, ATP-sensitive potassium channels.