Department of Neurology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China; Laboratory of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China.
Laboratory of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China.
Neuropharmacology. 2024 Sep 1;255:110006. doi: 10.1016/j.neuropharm.2024.110006. Epub 2024 May 18.
Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to treat acute ischemic stroke, has recently been shown to exert efficacious neuroprotective effects. However, whether EDB can ameliorate cognitive deficits in AD currently remains unclear. To this end, we explored the effects of EDB on AD and its potential mechanisms using an AD animal model (male APP/PS1 mice) treated with EDB for 10 weeks starting at 6 months of age. Subsequent analyses revealed that EDB-treated APP/PS1 mice exhibited improved cognitive abilities compared to untreated APP/PS1 mice. Administration of EDB in APP/PS1 mice further alleviated neuropathological alterations of the hippocampus, including Aβ deposition, pyramidal cell karyopyknosis, and oxidative damage, and significantly decreased the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and COX-2 in the hippocampus of APP/PS1 mice. Transcriptome sequencing analysis demonstrated the critical role of the inflammatory reaction in EDB treatment in APP/PS1 mice, indicating that the alleviation of the inflammatory reaction by EDB in the hippocampus of APP/PS1 mice was linked to the action of the TREM2/TLR4/MAPK signaling pathway. Further in vitro investigations showed that EDB suppressed neuroinflammation in LPS-stimulated BV2 cells by inhibiting the TLR4/MAPK signaling pathway and upregulating TREM2 expression. Thus, the findings of the present study demonstrate that EDB is a promising therapeutic agent for AD-related cognitive dysfunction.
目前，尚无有效的治疗药物可用于治疗阿尔茨海默病（AD）。然而，依达拉奉右莰醇（EDB）是一种新型的用于治疗急性缺血性脑卒中的复合药物，最近已显示出有效的神经保护作用。然而，EDB 是否能改善 AD 的认知障碍目前尚不清楚。为此，我们使用 AD 动物模型（6 月龄起接受 EDB 治疗 10 周的雄性 APP/PS1 小鼠）探索了 EDB 对 AD 的影响及其潜在机制。随后的分析表明，与未治疗的 APP/PS1 小鼠相比，EDB 治疗的 APP/PS1 小鼠的认知能力得到了改善。在 APP/PS1 小鼠中给予 EDB 进一步减轻了海马体的神经病理改变，包括 Aβ 沉积、锥体细胞核固缩和氧化损伤，并显著降低了 APP/PS1 小鼠海马体中炎症细胞因子（IL-1β、IL-6 和 TNF-α）和 COX-2 的水平。转录组测序分析表明炎症反应在 EDB 治疗 APP/PS1 小鼠中的关键作用，表明 EDB 在 APP/PS1 小鼠海马体中减轻炎症反应与 TREM2/TLR4/MAPK 信号通路的作用有关。进一步的体外研究表明，EDB 通过抑制 TLR4/MAPK 信号通路和上调 TREM2 表达来抑制 LPS 刺激的 BV2 细胞中的神经炎症。因此，本研究的结果表明，EDB 是一种有前途的 AD 相关认知功能障碍的治疗药物。
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