Kaur Harpreet, Kumar Amit, Jaggi Amteshwar S, Singh Nirmal
CNS Research Lab, Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
CNS and CVS Research Lab, Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
J Surg Res. 2015 Jul;197(1):191-200. doi: 10.1016/j.jss.2015.03.010. Epub 2015 Mar 16.
Cerebral ischemia-reperfusion (I-R) injury is one of the primary causes of ischemic stroke. Ischemic postconditioning (iPoCo) is evolving as an important adaptive technique to contain I-R injury. Some recent studies have shown neuroprotective effects of iPoCo. However, the neuroprotective mechanism of iPoCo is not clear. So, the present study has been undertaken to investigate the possible role of Sirtinol, a selective class III histone deacetylase (HDAC) inhibitor in the neuroprotective mechanism of iPoCo in mice.
Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was used to produce I-R-induced cerebral injury in Swiss albino mice. iPoCo involving three episodes of 10-s carotid artery occlusion and reperfusion instituted immediately after BCAO just before prolonged reperfusion of 24 h. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using a Morris water maze test. Rotarod test, inclined beam-walking test, and neurologic severity score (NSS) were used to assess motor incoordination. Acetylcholine esterase levels, brain thiobarbituric acid reactive species (TBARS), and glutathione level were also estimated.
BCAO for 12 min followed by reperfusion for 24 h produced a significant rise in cerebral infarct size and NSS along with impairment of memory and motor coordination and biochemical alteration (↑acetylcholine esterase, ↓glutathione, and ↑TBARS). iPoCo, involving three episodes of 10-s carotid artery occlusion with intermittent reperfusion of 10 s applied just after ischemic insult of 12 min produced a significant decrease in cerebral infarct size and NSS along with the reversal of I-R-induced impairment of memory and motor coordination. iPoCo-induced neuroprotective effects were significantly abolished by pretreatment with selective SIRT 1 (class III HDAC) blocker Sirtinol (10 mg/kg intraperitoneal).
It may be concluded that the neuroprotective effect of iPoCo probably involves activation of SIRT 1 (class III HDAC) enzyme.
脑缺血再灌注（I-R）损伤是缺血性脑卒中的主要病因之一。缺血后处理（iPoCo）正逐渐成为一种控制I-R损伤的重要适应性技术。最近的一些研究显示了iPoCo的神经保护作用。然而，iPoCo的神经保护机制尚不清楚。因此，本研究旨在探讨西妥昔单抗（一种选择性III类组蛋白去乙酰化酶（HDAC）抑制剂）在小鼠iPoCo神经保护机制中的可能作用。
采用双侧颈总动脉闭塞（BCAO）12分钟，随后再灌注24小时的方法，在瑞士白化小鼠中诱导I-R所致的脑损伤。iPoCo包括在BCAO后立即进行3次每次10秒的颈总动脉闭塞和再灌注，然后进行24小时的长时间再灌注。使用氯化三苯基四氮唑染色测量脑梗死体积。使用莫里斯水迷宫试验评估记忆力。采用转棒试验、倾斜梁行走试验和神经功能严重程度评分（NSS）评估运动不协调情况。还测定了乙酰胆碱酯酶水平、脑硫代巴比妥酸反应性物质（TBARS）和谷胱甘肽水平。
BCAO 12分钟后再灌注24小时导致脑梗死体积和NSS显著增加，同时伴有记忆力和运动协调性受损以及生化改变（乙酰胆碱酯酶升高、谷胱甘肽降低和TBARS升高）。iPoCo包括在12分钟缺血损伤后立即进行3次每次10秒的颈总动脉闭塞并间歇再灌注10秒，可使脑梗死体积和NSS显著降低，同时逆转I-R所致的记忆力和运动协调性损伤。用选择性SIRT 1（III类HDAC）阻滞剂西妥昔单抗（10 mg/kg腹腔注射）预处理可显著消除iPoCo诱导的神经保护作用。
可以得出结论，iPoCo的神经保护作用可能涉及SIRT 1（III类HDAC）酶的激活。
