中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (1): 189-193.doi: 10.4103/1673-5374.343888

• 原著:退行性病与再生 • 上一篇    下一篇

拉莫三嗪可能是治疗阿尔茨海默病的潜在药物

  

  • 出版日期:2023-01-15 发布日期:2022-06-17
  • 基金资助:

    国家自然科学基金项目（81771140）；江苏省自然科学基金项目（BK20201117）；江苏省国家杰出医学人才“六一工程”项目（LGY2020013）

Lamotrigine protects against cognitive deficits, synapse and nerve cell damage, and hallmark neuropathologies in a mouse model of Alzheimer’s disease

Xin-Xin Fu1, #, Rui Duan2, #, Si-Yu Wang2, Qiao-Quan Zhang3, Bin Wei2, Ting Huang2, Peng-Yu Gong2, Yan E2, Teng Jiang2, *, Ying-Dong Zhang1, 2, *   

  1. 1School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, China; 2Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China; 3Department of Pathology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
  • Online:2023-01-15 Published:2022-06-17
  • Contact: Teng Jiang, MD, PhD, jiang_teng@njmu.edu.cn; Ying-Dong Zhang, MD, PhD, zhangyingdong@njmu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81771140 (to YDZ); the Natural Science Foundation of Jiangsu Province of China, No. BK20201117 (to YDZ); and Jiangsu “Six One Project” for Distinguished Medical Scholars of China, No. LGY2020013 (to TJ).

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摘要：

拉莫三嗪是一种广泛用于治疗癫痫的药物。新的临床证据表明，拉莫三嗪能改善阿尔茨海默病患者的认知功能，然而其分子机制尚不明朗。此次实验对5月龄APP/PS1阿尔茨海默病小鼠模型连续3个月每天灌胃30 mg/kg拉莫三嗪，发现拉莫三嗪能明显改善模型小鼠的空间认知功能，减轻大脑内突触和神经细胞的损伤，同时减轻大脑中淀粉样蛋白β水平、tau过度磷酸化和神经炎症。进一步高通量RNA测序证实，拉莫三嗪治疗阿尔茨海默病的作用可能通过调节大脑中Ptgds，Cd74，Map3k1，Fosb和Spp1基因的表达而实现。实验进一步揭示了拉莫三嗪治疗阿尔茨海默病的分子机制，并认为拉莫三嗪可能是治疗阿尔茨海默病的潜在药物。

https://orcid.org/0000-0003-4170-1156 (Teng Jiang); https://orcid.org/0000-0001-7803-5367 (Ying-Dong Zhang)

关键词:

阿尔茨海默病, 拉莫三嗪, APP/PS1小鼠, 认知障碍, 突触损伤, 神经细胞损伤, 神经病理学, 淀粉样蛋白β, Tau过度磷酸化, 神经炎症, 高通量RNA测序

Abstract: Lamotrigine (LTG) is a widely used drug for the treatment of epilepsy. Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease. However, the underlying molecular mechanisms remain unclear. In this study, amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice were used as a model of Alzheimer’s disease. Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months. The cognitive functions of animals were assessed using Morris water maze. Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay. The cell damage in the brain was investigated using hematoxylin and eosin staining. The levels of amyloid-β and the concentrations of interleukin-1β, interleukin-6 and tumor necrosis factor-α in the brain were measured using enzyme-linked immunosorbent assay. Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction. We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice; alleviated damage to synapses and nerve cells in the brain; and reduced amyloid-β levels, tau protein hyperphosphorylation, and inflammatory responses. High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds, Cd74, Map3k1, Fosb, and Spp1 expression in the brain. These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease. Furthermore, these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.

Key words: Alzheimer’s disease, Alzheimer’s disease-related neuropathologies, amyloid-β pathology, APP/PS1 mice, cognitive deficits, damage of synapses and nerve cells, high-throughput RNA sequencing, lamotrigine, neuroinflammation, tau protein hyperphosphorylation