Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Fundam Clin Pharmacol. 2021 Feb;35(1):97-112. doi: 10.1111/fcp.12585. Epub 2020 Aug 27.
Recent studies raise the possibility that donepezil can delay the progression of Alzheimer's disease (AD). This research evaluated the efficacy of donepezil in an animal model with brain insulin resistance and AD-like alterations. Rats were fed with high-fat/high-fructose (HF/Hfr) diet during the study period (17 weeks) and received one injection of streptozotocin (STZ) (25 mg/kg) after 8 weeks of starting the study. Diabetic (T2D) rats were treated with donepezil (4 mg/kg; p.o.) or vehicle for 8 weeks after STZ injection. The influence of donepezil on AD-related behavioral, biochemical, and neuropathological changes was investigated in T2D rats. Treatment of diabetic rats with donepezil led to a significant decrease in both amyloid-β deposition and the raised hippocampal activity of cholinesterase (ChE). It significantly increased the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). It also improved cognitive dysfunction in the passive avoidance and the Morris water maze tests. However, donepezil treatment did not significantly decrease the elevated levels of P-tau, caspase-3, GSK-3β, MDA, TNF-α, and IL-1β in the hippocampus of diabetic rats. Also, it did not restore the suppressed levels of glutathione and superoxide dismutase in the brain of these rats. Moreover, donepezil did not alter the elevated serum level of glucose, insulin, and total cholesterol. These findings suggest that donepezil treatment could ameliorate learning and memory impairment in T2D rats through reversal of some of the AD-related alterations, including reduction of amyloid-β burden and ChE activity as well as restoration of glutamate receptor expression. However, lack of any significant effect on P-tau load, oxidative stress, neuroinflammation, and insulin resistance raises the question about the ability of donepezil to delay the development or arrest the progression of T2D-induced AD and it is still a matter of debate that requires further studies.
最近的研究提出了多奈哌齐可能延缓阿尔茨海默病（AD）进展的可能性。这项研究评估了多奈哌齐在具有脑胰岛素抵抗和 AD 样改变的动物模型中的疗效。在研究期间（17 周），大鼠给予高脂肪/高果糖（HF/HFr）饮食，在研究开始后 8 周接受链脲佐菌素（STZ）（25mg/kg）一次注射。糖尿病（T2D）大鼠在 STZ 注射后用多奈哌齐（4mg/kg；po）或载体治疗 8 周。研究了多奈哌齐对 T2D 大鼠 AD 相关行为、生化和神经病理学变化的影响。用多奈哌齐治疗糖尿病大鼠可显著减少淀粉样β沉积和海马胆碱酯酶（ChE）活性升高。它还显著增加了抑制的谷氨酸受体表达（AMPA GluR1 亚基和 NMDA 受体亚基 NR1、NR2A、NR2B）。它还改善了被动回避和 Morris 水迷宫测试中的认知功能障碍。然而，多奈哌齐治疗并未显著降低糖尿病大鼠海马中升高的 P-tau、caspase-3、GSK-3β、MDA、TNF-α和 IL-1β水平。此外，它也未能恢复这些大鼠大脑中抑制的谷胱甘肽和超氧化物歧化酶水平。此外，多奈哌齐并未改变升高的血清葡萄糖、胰岛素和总胆固醇水平。这些发现表明，多奈哌齐治疗可通过逆转 AD 相关改变来改善 T2D 大鼠的学习和记忆障碍，包括减轻淀粉样β负担和 ChE 活性以及恢复谷氨酸受体表达。然而，多奈哌齐对 P-tau 负荷、氧化应激、神经炎症和胰岛素抵抗没有任何显著影响，这引发了关于多奈哌齐能否延缓 T2D 诱导的 AD 发展或阻止其进展的问题，这仍然是一个需要进一步研究的争议问题。
