Department of Experimental Animal Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Lab for Aging Research, Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Exp Physiol. 2020 May;105(5):852-863. doi: 10.1113/EP088394. Epub 2020 Apr 3.
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.
Remote 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.
本研究的核心问题是什么？远程肝脏缺血预处理（RLIPC）能否保护大鼠脑免受脑缺血再灌注损伤？主要发现及其重要性是什么？预处理 RLIPC 可减少脑梗死体积，改善神经功能结局并抑制神经元凋亡。RLIPC 导致 AKT 磷酸化增加，而 AKT 抑制则消除 RLIPC 的作用。我们的数据表明，肝脏缺血预处理通过激活 AKT 依赖性途径对脑缺血再灌注损伤产生强烈的神经保护作用。
已证明远程肢体缺血预处理对保护大脑免受缺血再灌注（I/R）损伤具有有益作用。但是，对于远程肝脏缺血预处理（RLIPC）的效果知之甚少。因此，我们研究了 RLIPC 对遭受 I/R 损伤的脑组织的影响。大鼠随机分为假手术组、对照组或 RLIPC 组。除假手术组外，所有组的大鼠均接受大脑中动脉闭塞（MCAO）1 小时，然后再灌注 48 小时。对于 RLIPC 大鼠，在脑缺血前进行了 4 个周期的 5 分钟肝脏缺血（门静脉、肝动脉和静脉干闭塞），随后进行 5 分钟间歇性再灌注。再灌注 48 小时后评估梗死体积。采集血样进行血清乳酸脱氢酶（LDH）和肌酸激酶-MB（CK-MB）检测。测定皮质组织的形态变化和细胞凋亡。取右皮质组织进行 Western blot 测量。我们的数据表明，RLIPC 减轻了脑 I/R 损伤，减少了 MCAO 诱发的梗死区体积，降低了血清 LDH 和 CK-MB 水平，并减轻了 I/R 损伤后的神经功能缺损和细胞凋亡。此外，接受 RLIPC 的大鼠表现出皮质 AKT 磷酸化增加，但 SAFE 信号通路中的蛋白磷酸化水平没有变化。因此，用渥曼青霉素抑制 AKT 消除了肝脏预处理的神经保护作用。本研究首次表明，肝脏缺血预处理通过激活 AKT 依赖性途径有效保护大脑免受脑 I/R 损伤。
