GJ-4对冈田酸诱发小鼠学习记忆障碍的神经保护作用和机制研究

Neuroprotective and mechanistic study of GJ-4 on okadaic acid-induced memory impairment in mice

GJ-4是从中药栀子中提取出的藏红花色素类活性成分,前期研究发现GJ-4对Aβ诱发的小鼠学习记忆障碍具有明显的改善作用。本实验采用小鼠侧脑室注射冈田酸(okadaic acid, OA)建立记忆损伤模型(实验中所有操作均获得中国医学科学院北京协和医学院实验动物伦理委员会的批准,批准号:00000318),探讨GJ-4对Tau蛋白过度磷酸化引起神经元病变的改善作用及其机制。小鼠OA侧脑室注射后,连续16天灌胃给予GJ-4。结果显示, GJ-4可显著改善OA诱发的小鼠学习记忆障碍,同时减少小鼠海马区神经元尼氏小体的丢失。GJ-4可提高蛋白磷酸酶2A (protein phosphatase 2A, PP2A)活性并抑制糖原合成酶激酶-3β (glycogen synthase kinase-3β, GSK-3β)表达,进而降低Tau蛋白Ser396、Thr231和Ser404位点的磷酸化水平。进一步研究发现, GJ-4还可降低OA小鼠脑内氧化应激水平和海马星形胶质细胞活化介导的神经炎症而抑制神经元凋亡,最终发挥改善小鼠学习记忆障碍的作用。以上研究表明, GJ-4具有开发成为治疗阿尔茨海默症新药的良好前景。

GJ-4 is crocin enrichments extracted from Gardenia jasminoides J.Ellis,and our previous studies have shown that GJ-4 significantly improved learning and memory impairment induced by Aβin mice.Herein,a memory deficit model was developed by injecting okadaic acid(OA)into the lateral ventricle of mice,and the neuroprotection and underlying mechanism of GJ-4 on neuronal injury caused by Tau hyperphosphorylation were investigated.The Animal Care&Welfare Committee,Institute of Materia Medica,CAMS&PUMC has approved all procedures(No.00000318).GJ-4 at different doses was intragastric administration to mice for 16 days.Step-down test and Morris water maze test showed that GJ-4 could significantly improve OA-induced memory impairment in mice,and reduced the loss of Nissl bodies in the hippocampus of mice.GJ-4 could also decrease the phosphorylation level of Tau protein at Ser396,Thr231 and Ser404 via increasing protein phosphatase 2A(PP2A)activity and inhibiting glycogen synthase kinase-3β(GSK-3β)activity.Besides,further researches indicated that GJ-4 could inhibit the level of oxidative stress in the brain of OA mice,reduce neuronal apoptosis and inhibit the neuroinflammation mediated by activation of astrocytes in the hippocampus of mice,and eventually achieve its effects in improving learning and memory impairment in mice.According to these findings,we anticipated that GJ-4 might be a potential therapeutic drug for Alzheimer's disease.