Protective Effect of Delayed Remote Limb Ischemic Postconditioning: Role of Mitochondrial K_ATP Channels in a Rat Model of Focal Cerebral Ischemic Reperfusion Injury

Abstract

Delayed remote ischemic postconditioning (DRIPost) has been shown to protect the rat brain from ischemic injury. However, extremely short therapeutic time windows hinder its translational use and the mechanism of action remains elusive. Because opening of the mitochondria KATP channel is crucial for cell apoptosis, we hypothesized that the neuroprotective effect of DRIPost may be associated with KATP channels. In the present study, the neuroprotective effects of DRIPost were investigated using adult male Sprague-Dawley rats. Rats were exposed to 90 minutes of middle cerebral artery occlusion followed by 72 hours of reperfusion. Delayed remote ischemic postconditioning was performed with three cycles of bilateral femoral artery occlusion/reperfusion for 5 minutes at 3 or 6 hours after reperfusion. Neurologic deficit scores and infarct volumes were assessed, and cellular apoptosis was monitored by terminal deoxynucleotidyl transferase nick-end labeling. Our results showed that DRIPost applied at 6 hours after reperfusion exerted neuroprotective effects. The KATP opener, diazoxide, protected rat brains from ischemic injury, while the KATP blocker, 5-hydroxydecanote, reversed the neuroprotective effects of DRIPost. These findings indicate that DRIPost reduces focal cerebral ischemic injury and that the neuroprotective effects of DRIPost may be achieved through opening of KATP channels.

Ischemic Postconditioning Relieves Cerebral Ischemia and Reperfusion Injury Through Activating T-LAK Cell–Originated Protein Kinase/Protein Kinase B Pathway in Rats

“…1 A remarkably neuroprotective role for both remote IPostC and brain IPostC have been demonstrated by us and other groups. [2][3][4][5] Oxidative stress from reactive oxygen species has long been considered as a key deleterious factor in cerebral I/R injury, 6 and one of the mechanisms of IPostC against I/R injury is its antioxidative function. 7 The phosphoinositide 3-kinase/Akt signaling pathway is a classical neuroprotective pathway against I/R injury and is involved in the antioxidative effect of limb remote IPostC.…”

Remote Limb Perconditioning and Postconditioning

“…22,34,46 Moreover, blocking the mito-K ATP channel abolished the protective effect of remote limb conditioning in focal cerebral ischemia. 20 These pathways may be operative not only in brain but also in the brain endothelium.…”

“…19 Bilateral femoral occlusion for 3 cycles of both 5 and 8 minutes was effective at reducing infarct size when delayed 3 hours and as late as 6 hours after reperfusion, in a rat temporary MCA suture occlusion model. 20 Mechanical stroke occlusion models may have limited application to the human clinical situation, in which spontaneous recanalization and tissue plasminogen activator (tPA)-induced recanalization lead to a more gradual return of cerebral blood flow (CBF), different than that which occurs with an abrupt withdrawal of a suture. 21 In a mouse thromboembolic model, remote perconditioning with 5 cycles of 5-minute occlusion applied to the femoral artery at 2 hours after ischemia improved relative CBF, reduced infarct size, and improved functional outcome at 48 hours after stroke.…”

Remote Limb Ischemic Preconditioning: A Neuroprotective Technique in Rodents

“…The survival of most, perhaps all, tissues in the face of metabolic stress can be improved by prior conditioning with a period of sublethal ischemia 1,2 . Ischemic preconditioning (IP) in practical terms is the exposure of tissue to sublethal ischemia, before the tissue experiences more severe stressors, such as a subsequent ischemic insult.…”

“…In invasive limb ischemic studies for the study of brain and skin protection, ischemia is induced by separating the femoral artery from the groin ligaments and clamping the femoral artery 2,15,18 .…”