Ucf-101 可预防脓毒症大鼠的脑氧化损伤和认知障碍。
Ucf-101 protects against cerebral oxidative injury and cognitive impairment in septic rat.
机构信息
Department of Intensive Care Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
出版信息
Int Immunopharmacol. 2013 May;16(1):108-13. doi: 10.1016/j.intimp.2013.03.019. Epub 2013 Apr 2.
BACKGROUND
Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent and caspase-independent cell apoptosis. It has been verified that Omi/HtrA2 is related to apoptosis due to oxidative stress, which may play an important role in the integrity of mitochondria. Ucf-101 is a specific inhibitor of Omi/HtrA2 and it has been demonstrated that Ucf-101 has organ protective effects in a variety of in vitro and in vivo studies. The aim of our study was to examine the neuroprotective effects of Ucf-101 on cerebral oxidative injury and cognitive impairment in septic rats.
METHODS
Male Sprague Dawley rats are subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy. Rats were divided into 4 groups: (1) a sham group plus normal saline (10 mL/kg); (2) a sham group plus Ucf-101 (10 umol/kg); (3) CLP plus normal saline (10 mL/kg); and (4) CLP plus Ucf-101 (10 umol/kg). Brain tumor necrosis factor (TNF)-α level, caspase-3 and caspase-9 activities, malondialdehyde (MDA) content and catalase (CAT) activities were examined. TUNEL staining was utilized to evaluate the amount of apoptosis and the cognitive function was evaluated by the MWM test. The study also assessed the clinical scores of animals and the survival time for the 7-day period.
RESULTS
CLP resulted in a poor survival rate, evidence of hippocampal oxidative injury, cell apoptosis and cognitive dysfunction as well as elevated TNF-α level and caspases activities, increased weight loss and clinical scores. Ucf-101 pre-treatment could significantly inhibit caspases activities and cell apoptosis, reduce TNF-α and MDA levels, slightly reverse CAT activities in the brain and attenuate this CLP effect on cognitive dysfunction. In addition, the survival rate and survival time was significantly improved by pre-treatment with Ucf-101.
CONCLUSIONS
The present results demonstrated that ucf-101 has the neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats.
背景
Omi/HtrA2 是一种参与半胱天冬酶依赖性和非依赖性细胞凋亡的促凋亡线粒体丝氨酸蛋白酶。已经证实 Omi/HtrA2 与氧化应激引起的细胞凋亡有关，它可能在维持线粒体完整性方面发挥重要作用。Ucf-101 是 Omi/HtrA2 的特异性抑制剂，在各种体外和体内研究中已证明 Ucf-101 具有器官保护作用。本研究旨在探讨 Ucf-101 对脓毒症大鼠脑氧化损伤和认知障碍的神经保护作用。
方法
雄性 Sprague Dawley 大鼠行盲肠结扎穿孔术（CLP）或假手术剖腹术。大鼠分为 4 组：（1）假手术组加生理盐水（10 mL/kg）；（2）假手术组加 Ucf-101（10 μmol/kg）；（3）CLP 组加生理盐水（10 mL/kg）；（4）CLP 组加 Ucf-101（10 μmol/kg）。检测脑肿瘤坏死因子（TNF）-α水平、半胱天冬酶-3 和半胱天冬酶-9 活性、丙二醛（MDA）含量和过氧化氢酶（CAT）活性。TUNEL 染色评估凋亡细胞数量，MWM 试验评估认知功能。还评估了动物的临床评分和 7 天的存活时间。
结果
CLP 导致生存率降低，海马氧化损伤、细胞凋亡和认知功能障碍证据，TNF-α水平和半胱天冬酶活性升高，体重减轻和临床评分增加。Ucf-101 预处理可显著抑制半胱天冬酶活性和细胞凋亡，降低 TNF-α和 MDA 水平，轻度逆转脑 CAT 活性，并减轻 CLP 对认知功能障碍的影响。此外，Ucf-101 的预处理显著提高了生存率和存活时间。
结论
本研究结果表明，Ucf-101 对脓毒症大鼠脑氧化损伤和认知障碍具有神经保护作用。
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