Faculty of Pharmacy, Department of Pharmacology and Toxicology, Menoufia University, Menoufia, 32511, Egypt.
Faculty of Pharmacy, Department of Pharmacology and Toxicology, Cairo University, ElKasr Elaini Street, Cairo, 11562, Egypt.
J Neuroimmune Pharmacol. 2024 Jul 29;19(1):39. doi: 10.1007/s11481-024-10140-y.
Sporadic Alzheimer's disease (SAD) represents a major health concern especially among elderly. Noteworthy, neuroinflammation and oxidative stress are highly implicated in AD pathogenesis resulting in enhanced disease progression. Moreover, most of the available anti-Alzheimer drugs have several adverse effects with variable efficacy, therefore new strategies, including agents with anti-inflammatory and antioxidant effects, are encouraged. Along these lines, canagliflozin (CAN), with its anti-inflammatory and anti-apoptotic activities, presents a promising candidate for AD treatment. Therefore, this study aimed to evaluate the therapeutic potential of CAN via regulation of AMPK/SIRT-1/BDNF/GSK-3β signaling pathway in SAD. SAD model was induced by intracerebroventricular streptozotocin injection (ICV-STZ;3 mg/kg, once), while CAN was administered (10 mg/kg/day, orally) to STZ-treated mice for 21 days. Behavioral tests, novel object recognition (NOR), Y-Maze, and Morris Water Maze (MWM) tests, histopathological examination, total adenosine monophosphate-activated protein kinase (T-AMPK) expression, p-AMPK, and silent information regulator-1 (SIRT-1) were evaluated. Furthermore, brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3β (GSK-3β), acetylcholinesterase (AChE), Tau protein, insulin-degrading enzyme (IDE), nuclear factor erythroid-2 (Nrf-2), interleukin-6 (IL-6), nuclear factor kappa-B-p65 (NFκB-p65), beta-site APP cleaving enzyme 1 (BACE-1), and amyloid beta (Aβ) plaque were assessed. CAN restored STZ-induced cognitive deficits, confirmed by improved behavioral tests and histopathological examination. Besides, CAN halted STZ-induced neurotoxicity through activation of p-AMPK/SIRT-1/BDNF pathway, subsequently reduction of GSK-3β, Tau protein, AChE, NFκB-p65, IL-6, BACE-1, and Aβ plaque associated with increased IDE and Nrf-2. Consequentially, our findings assumed that CAN, via targeting p-AMPK/SIRT-1 pathway, combated neuroinflammation and oxidative stress in STZ-induced AD. Thus, this study highlighted the promising effect of CAN for treating AD.
散发性阿尔茨海默病（SAD）是老年人面临的一个主要健康问题。值得注意的是，神经炎症和氧化应激在 AD 的发病机制中起着重要作用，导致疾病进展加速。此外，大多数现有的抗阿尔茨海默病药物都有多种不良反应，疗效也各不相同，因此鼓励采用新的策略，包括具有抗炎和抗氧化作用的药物。沿着这条线，坎格列净（CAN）具有抗炎和抗细胞凋亡作用，是治疗 AD 的有前途的候选药物。因此，本研究旨在通过调节 AMPK/SIRT-1/BDNF/GSK-3β信号通路，评估 CAN 在 SAD 中的治疗潜力。SAD 模型通过侧脑室注射链脲佐菌素（ICV-STZ；3mg/kg，一次）诱导，同时给予 CAN（10mg/kg/天，口服）治疗 STZ 处理的小鼠 21 天。进行行为测试，新物体识别（NOR）、Y 迷宫和 Morris 水迷宫（MWM）测试、组织病理学检查、总腺苷单磷酸激活蛋白激酶（T-AMPK）表达、p-AMPK 和沉默信息调节因子-1（SIRT-1）。此外，还评估了脑源性神经营养因子（BDNF）、糖原合酶激酶-3β（GSK-3β）、乙酰胆碱酯酶（AChE）、Tau 蛋白、胰岛素降解酶（IDE）、核因子红细胞 2（Nrf-2）、白细胞介素-6（IL-6）、核因子κB-p65（NFκB-p65）、β-位淀粉样前体蛋白裂解酶 1（BACE-1）和淀粉样β（Aβ）斑块。CAN 恢复了 STZ 诱导的认知障碍，通过改善行为测试和组织病理学检查得到证实。此外，CAN 通过激活 p-AMPK/SIRT-1/BDNF 通路，随后减少 GSK-3β、Tau 蛋白、AChE、NFκB-p65、IL-6、BACE-1 和 Aβ斑块，同时增加 IDE 和 Nrf-2，阻止了 STZ 诱导的神经毒性。因此，我们的研究结果表明，CAN 通过靶向 p-AMPK/SIRT-1 通路，对抗 STZ 诱导的 AD 中的神经炎症和氧化应激。因此，本研究强调了 CAN 治疗 AD 的有希望的效果。
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