Remote liver ischaemic preconditioning protects rat brain against cerebral ischaemia–reperfusion injury by activation of an AKT‐dependent pathway

Abstract

New Findings What is the central question of this study? Can remote liver ischaemic preconditioning (RLIPC) protect rat brain against cerebral ischaemia–reperfusion injury? What is the main finding and its importance? Pretreatment with RLIPC reduced cerebral infarct volume, improved neurological outcomes and inhibited neuron apoptosis. RLIPC led to increased phosphorylation of AKT, while inhibition of AKT abolished the effects of RLIPC. Our data suggest that liver ischaemic preconditioning exerts a strong neuroprotective effect against cerebral ischaemia–reperfusion injury by activating an AKT‐dependent pathway. AbstractRemote limb ischaemic preconditioning has been shown to have beneficial effects in protecting brains against ischaemia–reperfusion (I/R) injury. However, little is known regarding the effect of remote liver ischaemic conditioning (RLIPC). We therefore investigated the effect of RLIPC on brain tissues suffering from I/R injury. Rats were randomly assigned to a sham group, a control group or a RLIPC group. Rats in all groups except for the sham group received middle cerebral artery occlusion (MCAO) for 1 h, followed by 48 h of reperfusion. For the RLIPC rats, four cycles of 5 min of liver ischaemia (portal vein, hepatic arterial and venous trunk occlusion) with 5 min intermittent reperfusion were carried out before cerebral ischaemia. Infarct volume was assessed after 48 h of reperfusion. Blood samples were taken for serum lactate dehydrogenase (LDH) and creatine kinase‐MB (CK‐MB) tests. Morphological changes of cortical tissue and cellular apoptosis were determined. Right cortex tissues were taken for western blotting measurements. Our data demonstrate that RLIPC reduced cerebral I/R injury, decreased the volume of the MCAO‐evoked infarct region, decreased serum levels of LDH and CK‐MB, and reduced neurological deficits and apoptosis after I/R injury. Moreover, rats receiving RLIPC showed increased cortical AKT phosphorylation, but protein phosphorylation level was unchanged in the survivor activating factor enhancement (SAFE) signalling pathway. Accordingly, inhibition of AKT with wortmannin abolished the neuroprotective action of liver preconditioning. Our study showed for the first time that liver ischaemic preconditioning effectively protects brain against cerebral I/R injury by activating an AKT‐dependent pathway.

Remote Liver Ischemic Preconditioning Attenuates Myocardial Ischemia/reperfusion Injury in Streptozotocin-induced Diabetic Rats

“…We previously found that RLIPC protected hearts against sudden cardiac death via activation of ERK1/2 pathway [10]. Meanwhile, we also observed increased phospho-AKT levels in the brainof RLIPC rats compared to controls [13]. However, in the current study, we found that pretreatment with liver I/R stimulus prior to LAD occlusion did not enhance ERK1/2 or AKT phosphorylation in diabetic or non-diabetic hearts.…”

“…Activation of reperfusion injury salvage kinase (RISK) pathway, or the survivor activating factor enhancement (SAFE)pathways can be involved in ischemic preconditioning and postconditioning [11,12]. We previously reported that RLIPC activated RISK pathway post I/R, speci cally, increased ERK1/2 [10], AKT [13], and GSK-3β [6] protein phosphorylation. Meanwhile, the inhibition of STAT3, the vital signal molecule in SAFE pathway, abolished the protective action of liver preconditioning [12].…”

Remote liver ischemic preconditioning attenuates myocardial ischemia/reperfusion injury in streptozotocin-induced diabetic rats

“…We previously found that RLIPC protected hearts against sudden cardiac death via activation of ERK1/2 pathway 10 . Meanwhile, we also observed increased phospho-AKT levels in the brain of RLIPC rats compared to controls 13 . However, results from literatures regarding whether AKT can be activated (phosphorylated) in diabetic myocardium are conflicting.…”

Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges

“…It has been evaluated that many organs or tissues, such as kidney ( 51 , 52 ), mesenteric artery ( 53 , 54 ), liver ( 55 , 56 ), and limbs ( 223 – 225 ), can be considered as remote conditioned sites. Obviously, the most convenient and safest strategy of performing RIPreC should be on limbs when this preconditioning strategy is considered to be clinically used ( 28 ).…”