Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, 210009, China.
School of Pharmacy, Nantong University, Nantong, 226001, Jiangsu, China.
J Neuroimmune Pharmacol. 2019 Sep;14(3):401-412. doi: 10.1007/s11481-018-09830-1. Epub 2019 Jan 11.
The neurotoxicity of Aβ peptides has been well documented, but effective neuroprotective approaches against Aβ neurotoxicity are unavailable. In the present study, we investigated effects of 1-Methylnicotinamide (MNA), known as a main metabolite of nicotinamide (NA), on the impairment of learning and memory induced by Aβ and the underlying mechanisms. We found that intragastric administration of MNA at 100 or 200 mg/kg for 3 weeks significantly reversed bilateral intrahippocampal injection of Aβ-induced cognitive impairments in the Morris water maze (MWM), Y-maze and Novel object recognition tests. Furthermore, MNA suppressed Aβ-induced neuroinflammation, characterized by suppressed activation of microglia, decreased the expression of IL-6, TNF-α and nuclear translocation of NF-κB p65, as well as attenuated neuronal apoptosis as indicated by decreased TUNEL-positive cells and ratio of caspase-3 fragment to procaspase-3, and increased ratio of Bcl-2/Bax in the hippocampus. Our results show that MNA may ameliorate Aβ-induced cognition deficits, which is involved in inhibition of neuroinflammation and apoptosis mediated by NF-κB signaling, suggesting that MNA could have potential therapeutic value for AD. Graphical Abstract Neuroprotective affect of MNA on Aβ-induced cognitive deficits.
Aβ 肽的神经毒性已有充分的文献记载，但目前还没有有效的针对 Aβ 神经毒性的神经保护方法。在本研究中，我们研究了 1-甲基烟酰胺（MNA）的作用，MNA 是烟酰胺（NA）的主要代谢物之一，研究其对 Aβ 引起的学习和记忆损伤的影响及其潜在机制。我们发现，连续 3 周每天灌胃给予 MNA（100 或 200mg/kg）可显著逆转双侧海马内注射 Aβ 引起的 Morris 水迷宫（MWM）、Y 迷宫和新物体识别测试中的认知障碍。此外，MNA 抑制了 Aβ 诱导的神经炎症，表现为小胶质细胞激活受到抑制、IL-6、TNF-α 的表达减少、NF-κB p65 核易位减少，以及 TUNEL 阳性细胞减少和 caspase-3 片段与 procaspase-3 的比值降低，同时海马中 Bcl-2/Bax 的比值增加。我们的结果表明，MNA 可能改善 Aβ 诱导的认知缺陷，这与 NF-κB 信号介导的神经炎症和细胞凋亡抑制有关，提示 MNA 可能对 AD 具有潜在的治疗价值。
