α-硫辛酸通过抑制JAK2/STAT3恢复GPX4改善侧脑室注射链脲菌素诱导的大鼠空间学习记忆障碍  

α-Lipoic acid improves spatial learning memory deficits induced by intracerebroventricular injection of streptozotocin via activation of JAK/STAT-GPX4 in rats

作　　者：张瑶 许腾 江燕丽 Zhang Yao;Xu Teng;Jiang Yanli(Endocrine Department,Liyuan Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430077,China)

机构地区：[1]华中科技大学同济医学院附属梨园医院内分泌科,武汉430077

出　　处：《中华内分泌代谢杂志》2023年第11期955-963,共9页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然基金重大研究计划资助项目(91949205);湖北省自然科学基金资助项目(2021CFB337)。

摘　　要：目的观察α-硫辛酸(ALA)对侧脑室注射(intracerebroventricular injection,icv)链脲菌素(streptozotocin,STZ)致大鼠学习记忆障碍的影响并探讨作用机制。方法45只雄性SD大鼠被随机分为3组,即对照组、icv-STZ组和icv-STZ+ALA组,每组15只。STZ通过大鼠侧脑室脑立体定位注射,ALA干预用灌胃法,对照组采用侧脑室注射人工脑脊液及生理盐水灌胃,灌胃4周后用Morris水迷宫检测大鼠的空间学习记忆能力。同时,用免疫组化方法检测小胶质细胞与星形胶质细胞数量,电子显微镜检测线粒体完整性,蛋白免疫印迹检测炎症因子、磷酸化Tau蛋白、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)和糖原合成酶激酶-3β(glycogen synthase kinase 3β,GSK-3β)的表达或活性水平。结果行为学检测结果显示,侧脑室注射STZ 4周后大鼠空间学习记忆能力显著下降,ALA干预可显著改善大鼠的空间学习记忆能力。多层面分子水平检测结果显示,STZ组大鼠海马组织铁离子水平显著升高,同时伴有脂质过氧化、线粒体完整性显著破坏、氧化还原系统失衡、胶质细胞数目增加、磷酸化的Tau蛋白水平显著升高、MAPK与GSK-3β通路激活。进一步检测发现,STZ激活Janus激酶2/信号转导与转录激活子3(JAK2/STAT3)通路,并转录抑制过氧化物酶GPX4表达。抑制STAT3活性则可阻断STZ诱导GPX4下调与Tau蛋白过度磷酸化。结论ALA通过抑制JAK2/STAT3通路,恢复GPX4蛋白水平,从而螯合铁离子、改善线粒体功能与脂质过氧化,平衡机体的氧化还原系统,降低Tau蛋白过度磷酸化,改善STZ诱导的大鼠空间学习记忆障碍。Objective To observe the effect ofα-lipoic acid(ALA)on the intracerebroventricular injection(icv)of streptozotocin(STZ)-induced spatial learning memory impairments in rats and the underlying molecular mechanisms.Methods Forty-five male SD rats were assigned into 3 groups,control group,icv-STZ group and icv-STZ+ALA group,15 rats each.STZ was dissolved in artificial cerebrospinal fluid then injected into the lateral ventricles of the rat by using stereotaxic device.ALA was administrated by gavage after STZ injection.The spatial learning memory was examined by using Morris water maze test after 4 weeks of treatment.Immunohistochemistry was performed to detect the number of microglia and astrocytes,electron microscopy was applied to detect mitochondrial integrity,Western blotting was used to detect the protein expression levels,and the changes of lipid peroxidation and redox system were examined by kit.Results Spatial learning memory was impaired in rats after 4 weeks of STZ injection,and ALA treatment ameliorated STZ-induced cognitive dysfunction in rats.Iron concentration,lipid peroxidation,neuroinflammation,Tau hyperphosphorylated were enhanced markedly after STZ injection,along with and the activation of MAPK and GSK-3β,which were ameliorated by ALA.Further examination revealed that STZ activated the JAK2/STAT3 pathway and transcriptionally inhibited the expression of peroxidase GPX.Inhibition of STAT3 activity can block STZ-induced downregulation of GPX4 and Tau hyperphosphorylation.Conclusion ALA ameliorated STZ-induced spatial learning memory impairments in rats via deactivation of JAK2/STAT3 pathway,restored GPX4 protein level,resulting in chelating iron,improving mitochondrial function,balancing the redox system,ameliorating Tau hyperphosphorylation and neuroinflammation.

关 键 词：Α-硫辛酸 GPX4 铁离子螯合剂 链脲菌素 散发型阿尔茨海默病 空间学习记忆障碍 

分 类 号：R965[医药卫生—药理学]