Institute of Traditional Chinese Medicine, Chengde Medical College, Hebei Province Key Research Office of Traditional Chinese Medicine Against Dementia, Hebei Province Key Laboratory of Traditional Chinese Medicine Research and Development Hebei Key Laboratory of Nerve Injury and Repair, Chengde, Hebei 067000, China.
The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei 050011, China.
Comb Chem High Throughput Screen. 2022;25(5):919-933. doi: 10.2174/1386207324666210506152320.
The aim of this study was to investigate the effect and molecular mechanism of Scutellaria baicalensis Georgi stems and leaves flavonoids (SSF) in promoting neurogenesis and improving memory impairment induced by the PI3K-AKT-CREB signaling pathway.
Alzheimer's disease (AD) was induced in the male Wistar rats by intracerebroventricular injection of amyloid beta peptide 25-35 (Aβ) in combination with aluminum trichloride (AlCl3) and recombinant human transforming growth factor-β1(RHTGF-β1) (composited Aβ). The Morris water maze was used to screen the successful establishment of the memory impairment model of rats. The screened successful model rats were randomly divided into a model group and three groups of three different doses of the drug (SSF). Rats in the drug group were treated with 35, 70, and 140 mg/kg of SSF for 43 days. The Eight-arm maze was used to measure the spatial learning and memory abilities of the rat, including working memory errors (WME) and reference memory errors (RME). Immunohistochemistry was used to detect the expression of BrdU, an indicator of neuronal proliferation, in the hippocampal gyrus of rats. The mRNA and protein expressions of TRKB, PI3K, AKT, P-AKT, and IGF2 in the PI3K-AKT-CREB signaling pathway in the hippocampus and cerebral cortex of the rats were determined by quantitative real-time PCR (qPCR) and Western blotting methods.
Compared to the sham group, the spatial memory ability of rats with composited Aβ was decreased, the number of WME and RME (P < 0.01) was increased, the expression of BrdU protein (P < 0.01) in the hippocampal gyrus was reduced, the mRNA and protein expression levels of TRKB, AKT, and IGF2 (P < 0.01, P < 0.05) in the hippocampus and cerebral cortex were lowered, and the mRNA expression level of PI3K (P < 0.01) in the cerebral cortex and the protein expression level of PI3K (P < 0.01) in the hippocampus were augmented. However, compared to the model group, the three-doses of SSF improved memory disorder induced by composited Aβ, reduced the number of WME and RME, increased the expression of BrdU protein in the hippocampal gyrus, and differently regulated the mRNA and protein expressions in composited Aβ rats.
SSF improved memory impairment and neurogenesis disorder induced by composited Aβ in rats by activating the PI3K-AKT-CREB signaling pathway and up-regulating the mRNA and protein expressions of TRKB, PI3K, AKT, CREB, and IGF2.
本研究旨在探讨黄芩茎叶总黄酮（SSF）通过激活 PI3K-AKT-CREB 信号通路，促进神经发生，改善阿尔茨海默病（AD）大鼠学习记忆障碍的作用及分子机制。
采用脑室内注射淀粉样β肽 25-35（Aβ）联合三氯化铝（AlCl3）和重组人转化生长因子-β1（RHTGF-β1）（复合 Aβ）制备 AD 大鼠模型。Morris 水迷宫筛选大鼠记忆障碍模型建立成功。将筛选成功的模型大鼠随机分为模型组和 3 个不同剂量药物（SSF）组。药物组大鼠分别给予 35、70、140 mg/kg 的 SSF 连续灌胃 43 天。八臂迷宫检测大鼠空间学习记忆能力，包括工作记忆错误（WME）和参考记忆错误（RME）。免疫组织化学法检测大鼠海马齿状回 BrdU 表达，BrdU 是神经元增殖的指标。采用实时荧光定量 PCR（qPCR）和 Western blot 法检测大鼠海马和皮质组织中 PI3K-AKT-CREB 信号通路相关基因 TRKB、PI3K、AKT、P-AKT 和 IGF2 的 mRNA 和蛋白表达。
与假手术组比较，复合 Aβ 组大鼠空间记忆能力下降，WME 和 RME 增加（P＜0.01），海马齿状回 BrdU 蛋白表达减少（P＜0.01），海马和皮质组织中 TRKB、AKT 和 IGF2 的 mRNA 和蛋白表达水平降低（P＜0.01，P＜0.05），皮质组织中 PI3K 的 mRNA 表达水平升高（P＜0.01），海马组织中 PI3K 的蛋白表达水平升高（P＜0.01）。与模型组比较，SSF 各剂量均可改善复合 Aβ 所致大鼠记忆障碍，减少 WME 和 RME，增加海马齿状回 BrdU 蛋白表达，不同程度调节复合 Aβ 大鼠海马和皮质组织中基因和蛋白的表达。
SSF 通过激活 PI3K-AKT-CREB 信号通路，上调 TRKB、PI3K、AKT、CREB 和 IGF2 的 mRNA 和蛋白表达，改善复合 Aβ 诱导的大鼠学习记忆障碍和神经发生障碍。
