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米诺环素通过抑制炎症因子和谷氨酸转运体表达减轻缺氧所致新生鼠认知损伤

李虹椿, 肖婕, 黄益龙, 李龙君, 江虹, 黄丽轩, 杨婷, 杨泠, 李凡^*

昆明医科大学病理学与病理生理学系，昆明 650500

摘要

本研究旨在探讨米诺环素(minocycline)对新生大鼠缺氧后认知功能的影响及其可能的作用机制。取出生后1 d的Sprague Dawley (SD)大鼠，经系统性缺氧，构建缺氧性脑损伤(hypoxic brain damage, HBD)模型。缺氧结束后2 h，腹腔注射生理盐水(Hy组)或米诺环素(Hy + M组)，未造模的同龄大鼠为正常对照组(NG组)。各组大鼠出生后第30天用Y臂电子迷宫检测学习、记忆能力；缺氧后7 d用Western blot检测大鼠海马组织炎症介质(Iba-1、IL-1β、TNF-α和TGF-β1)、谷氨酸转运体(EAAT1和EAAT2)、总Tau及不同位点(Tyr18、Thr205、Thr231、Ser396和Ser404)磷酸化Tau蛋白的表达情况。结果显示，缺氧后大鼠学习、记忆能力显著下降，米诺环素处理后能改善其学习、记忆能力。缺氧后7 d，大鼠海马组织Iba-1、IL-1β、TNF-α、EAAT2和T231位点磷酸化的Tau蛋白表达升高，总Tau蛋白的表达下降；米诺环素处理后能降低缺氧后大鼠海马组织Iba-1、IL-1β、TNF-α和EAAT2的表达水平，但不能干预总Tau及磷酸化Tau蛋白的表达。以上结果提示，米诺环素能改善缺氧后大鼠认知功能障碍，其保护机制可能与其对脑内炎症反应和功能异常的谷氨酸转运体的抑制有关，但不涉及对Tau蛋白异常过度磷酸化的调节。

关键词： 米诺环素; 缺氧; 炎症反应; 谷氨酸转运体; Tau蛋白; 过度磷酸化; 认知功能

分类号：R3

[Reduction in hypoxia-derived neuroinflammation and dysfunctional glutamate transporters by minocycline may restore hypoxia-injured cognition of neonatal rat.] [Article in Chinese]

LI Hong-Chun, XIAO Jie, HUANG Yi-Long, LI Long-Jun, JIANG Hong, HUANG Li-Xuan, YANG Ting, YANG Ling, LI Fan^*

Department of Pathology and Pathophysiology, Kunming Medical University, Kunming 650500, China

Abstract

The aim of the present study was to investigate the effects of minocycline on cognitive functions in neonatal rat after hypoxia exposure and the underlying mechanism. A model of hypoxic brain damage (HBD) was developed by exposing postnatal 1 day (P1) rats to systemic hypoxia. The rats were intraperitoneally injected with normal saline (Hy group) or minocycline (Hy + M group) 2 h after hypoxia exposure. Some other P1 rats that were not subjected to systemic hypoxia were used as normal control (NG group). The Y-maze test was used to evaluate learning and memory ability on postnatal day 30. Inflammatory mediators (Iba-1, IL-1β, TNF-α and TGF-β1), glutamate transporters (EAAT1 and EAAT2), total Tau and phosphorylated Tau (phosphorylation sites: Tyr18, Thr205, Thr231, Ser396 and Ser404) protein expressions in the hippocampus were detected by Western blot 7 d after hypoxic exposure. The results showed that hypoxia induced learning and memory impairments of the neonatal rats, and minocycline administration could reverse the effects of hypoxia. The protein expression levels of Iba-1, IL-1β, TNF-α, EAAT2 and Tau phosphorylated at T231 were increased, but the total Tau expression was decreased in the hippocampus of the rats from Hy group 7 d after hypoxia exposure. In the hypoxia-treated rats, minocycline down-regulated Iba-1, IL-1β, TNF-α and EAAT2 protein expressions significantly, but did not affect total Tau and phosphorylated Tau protein expressions. Our results suggest that minocycline can prevent cognitive deficits of rats with hypoxia exposure, and the underlying mechanism may involve the inhibition of neuroinflammation and dysfunctional glutamate transporters but not the regulation of the Tau hyperphosphorylation.

Key words: minocycline; hypoxia; neuroinflammation; glutamate transporters; Tau protein; hyperphosphorylation; cognitive function

收稿日期：2015-11-30　　录用日期：2015-12-29

通讯作者：李凡　　E-mail: leefan623@sina.com

引用本文：

李虹椿, 肖婕, 黄益龙, 李龙君, 江虹, 黄丽轩, 杨婷, 杨泠, 李凡. 米诺环素通过抑制炎症因子和谷氨酸转运体表达减轻缺氧所致新生鼠认知损伤[J]. 生理学报 2016; 68 (2): 148-156.

LI Hong-Chun, XIAO Jie, HUANG Yi-Long, LI Long-Jun, JIANG Hong, HUANG Li-Xuan, YANG Ting, YANG Ling, LI Fan. [Reduction in hypoxia-derived neuroinflammation and dysfunctional glutamate transporters by minocycline may restore hypoxia-injured cognition of neonatal rat.] [Article in Chinese]. Acta Physiol Sin 2016; 68 (2): 148-156 (in Chinese with English abstract).