Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
National Agri-Food Biotechnology Institute (NABI), Sector-81, SAS Nagar, Mohali 140306, Punjab, India.
Brain Res Bull. 2020 Nov;164:83-97. doi: 10.1016/j.brainresbull.2020.08.001. Epub 2020 Aug 9.
Sporadic Alzheimer's disease (sAD) is the most common type of dementia and progressive neurodegenerative disease. To establish the sAD model, intracerebroventricular (ICV) streptozotocin (STZ) at a dose of 3 mg/kg was administered bilaterally in rats on a stereotaxic apparatus. Behavioral tests such as Morris water maze (MWM), novel object recognition (NOR) and open field test were performed to evaluate cognitive and locomotor functions. Two treatment doses (5 mg/kg and 10 mg/kg) of sodium orthovanadate (SOV) and rivastigmine (2 mg/kg) were given orally to ICV-STZ induced rats for 21 days. Cortical and hippocampal tissues were dissected. Estimation of oxidative stress, mitochondrial dysfunction as complex I, II, III, IV activity, cholinergic function as acetylcholinesterase activity, ELISA for phosphorylated tau protein and insulin degrading enzyme (IDE), neuroinflammation as NF-κB gene expression and insulin signaling functioning as Q-RT-PCR for IR, IRS-1, PI3K, AKT, GSK-3β gene expression were performed. Behavioral results with SOV and rivastigmine treatment revealed decreased escape latency and increased discrimination index in MWM and NOR respectively. Treatment results with SOV also demonstrated attenuation of oxidative imbalance, improved mitochondrial activity, and reversed IDE and tau pathology. SOV treatment upregulated gene expression of IR, IRS-1, PI3K, and AKT, and downregulated that of GSK-3β. SOV results were compared with standard drug rivastigmine. Conclusively, the memory enhancement by SOV was mediated through oxidative balance, mitochondrial enzyme complex activation, and improved insulin signaling regulation. However, the primary mechanism of SOV remained attenuation of tau pathology by the upregulation of IRS-1/PI3K/AKT/GSK-3β pathway and reversal of insulin resistance in terms of IDE. Hence, in sAD paradigm, SOV contributed to memory improvement evident with the findings of behavioral studies, which can further potentially have clinical significance in AD.
散发性阿尔茨海默病（sAD）是最常见的痴呆症和进行性神经退行性疾病。为了建立 sAD 模型，在立体定向仪上向大鼠双侧脑室内（ICV）给予 3mg/kg 的链脲佐菌素（STZ）。进行莫里斯水迷宫（MWM）、新物体识别（NOR）和旷场试验等行为测试，以评估认知和运动功能。将两种治疗剂量（5mg/kg 和 10mg/kg）的偏钒酸钠（SOV）和利斯的明（2mg/kg）口服给予 ICV-STZ 诱导的大鼠，持续 21 天。解剖皮质和海马组织。评估氧化应激、线粒体功能（复合物 I、II、III、IV 活性）、胆碱能功能（乙酰胆碱酯酶活性）、磷酸化 tau 蛋白和胰岛素降解酶（IDE）的 ELISA、神经炎症（NF-κB 基因表达）和胰岛素信号转导（IR、IRS-1、PI3K、AKT、GSK-3β基因表达的 Q-RT-PCR）。SOV 和利斯的明治疗的行为结果显示，MWM 和 NOR 中的逃避潜伏期减少，辨别指数增加。SOV 治疗结果还表明氧化失衡得到缓解，线粒体活性得到改善，IDE 和 tau 病理得到逆转。SOV 治疗上调了 IR、IRS-1、PI3K 和 AKT 的基因表达，下调了 GSK-3β 的基因表达。将 SOV 的结果与标准药物利斯的明进行比较。结论：SOV 通过氧化平衡、线粒体酶复合物激活和改善胰岛素信号调节来增强记忆。然而，SOV 的主要机制仍然是通过上调 IRS-1/PI3K/AKT/GSK-3β 通路和逆转 IDE 中的胰岛素抵抗来减轻 tau 病理学。因此，在 sAD 范式中，SOV 通过行为研究的发现改善了记忆，这可能在 AD 方面具有潜在的临床意义。
