Yang Xiaojing, Wang Ruonan, Zhou Hailun, Wang Li, Wang Rui, Li Haomin, Tan Baodong, Wu Qiong, Xu Xin, Cui Lianxu, Li Zaiyu, Li Hua
College of Pharmacy, Dalian Medical University, Dalian, China.
National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China.
Front Pharmacol. 2021 Nov 22;12:751028. doi: 10.3389/fphar.2021.751028. eCollection 2021.
Learning and memory impairment is a common clinical symptom of aging and nervous system injuries, and seriously affects quality of life. Memory impairment is associated with increased oxidative stress (OS) and inflammatory response. β-hydroxybutyrate (BHBA) is a water-soluble endogenous small-molecule ketone body that easily crosses the blood-brain barrier and has shown neuroprotection activities. In this study, we investigated the effects and mechanisms of BHBA on D-galactose (D-gal)-induced memory impairment in mice by and experiments. BHBA was administered intragastrically to D-gal-injured C57BL/6 mice for 42 days. Water maze performance, the morphology of the hippocampus with Nissl staining, the ACh content, OS, and inflammation status were examined. To further investigate the mechanism, hippocampal neuronal cells (HT22) were treated with BHBA with or without the SIRT1 inhibitor or small interfering RNAs against sirt1 (si-SIRT1) before incubation with D-gal. BHBA significantly improved water maze performance; increased the ACh content, SOD activity, and SIRT1 expression; and decreased AChE and LDH activity, ROS, MDA, IL-1β, TNF-α contents, and NLRP3 expression. Further studies with the SIRT inhibitor or siRNAs against sirt1 reversed the above effects of BHBA. Collectively, BHBA inhibited hippocampal OS and the inflammation process to alleviate learning and memory impairment through activating the SIRT1 pathway in D-gal-injured mice, suggesting that BHBA could be a potential option for drug development of learning and memory impairment induced by nervous system injuries.
学习和记忆障碍是衰老及神经系统损伤常见的临床症状，严重影响生活质量。记忆障碍与氧化应激（OS）增加及炎症反应相关。β-羟基丁酸（BHBA）是一种水溶性内源性小分子酮体，易通过血脑屏障，已显示出神经保护活性。在本研究中，我们通过[具体实验]研究了BHBA对D-半乳糖（D-gal）诱导的小鼠记忆障碍的影响及机制。对D-gal损伤的C57BL/6小鼠灌胃给予BHBA 42天。检测水迷宫行为学表现、尼氏染色观察海马形态、乙酰胆碱（ACh）含量、OS及炎症状态。为进一步探究机制，在与D-gal孵育前，用BHBA处理海马神经元细胞（HT22），同时加入或不加入SIRT1抑制剂或针对sirt1的小干扰RNA（si-SIRT1）。BHBA显著改善水迷宫行为学表现；增加ACh含量、超氧化物歧化酶（SOD）活性及SIRT1表达；降低乙酰胆碱酯酶（AChE）和乳酸脱氢酶（LDH）活性、活性氧（ROS）、丙二醛（MDA）、白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）含量及NLRP3表达。用SIRT抑制剂或针对sirt1的siRNAs进行的进一步研究逆转了BHBA的上述作用。总体而言，BHBA通过激活D-gal损伤小鼠的SIRT1通路抑制海马OS及炎症过程，以减轻学习和记忆障碍，提示BHBA可能是神经系统损伤所致学习和记忆障碍药物研发的一个潜在选择。
