Ma'anshan People's Hospital, Ma'anshan, 243000, China.
Anhui Medical University, Hefei, 230032, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 May;397(5):3065-3075. doi: 10.1007/s00210-023-02765-2. Epub 2023 Oct 25.
Pyroptosis-mediated neuron death plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). However, the effect of 1,7-diphenyl-4-hepten-3-one (C1), a natural diarylheptanoid, on AD is unclear. Herein, we investigated the therapeutic effect of C1 on APP/PS1 mice and β-amyloid (Aβ)-induced HT22 cells. Our findings showed that C1 attenuated cognitive impairment and mitigated pathological damage in APP/PS1 mice. Furthermore, we found that C1 prevented oxidative stress damage and decreased the levels of pyroptosis-related proteins. In vitro experiments showed that C1 can improve the proliferation of Aβ-induced HT22 cells and decrease the levels of pyroptosis-related proteins in them. When Nrf2 was silenced, the positive effects of C1 in inhibiting pyroptosis were inhibited. Particularly, the production of pyroptosis-associated proteins, including NLRP3, GSDMD, and caspase-1, and the secretion of pro-inflammatory molecules, including IL-1 and IL-18, were increased. Altogether, these findings indicate that C1 can mitigate AD-like pathology via the inhibition of pyroptosis by activating the Nrf2 pathway. We believe that this study can provide alternative strategies for the prevention and treatment of AD.
细胞焦亡介导的神经元死亡在神经退行性疾病中起着至关重要的作用，如阿尔茨海默病（AD）。然而，天然二芳基庚烷类化合物 1,7-二苯基-4-庚烯-3-酮（C1）对 AD 的影响尚不清楚。在此，我们研究了 C1 对 APP/PS1 小鼠和β-淀粉样蛋白（Aβ）诱导的 HT22 细胞的治疗作用。研究结果表明，C1 可减轻 APP/PS1 小鼠的认知障碍并减轻其病理损伤。此外，我们发现 C1 可预防氧化应激损伤并降低细胞焦亡相关蛋白的水平。体外实验表明，C1 可改善 Aβ诱导的 HT22 细胞的增殖，并降低其细胞焦亡相关蛋白的水平。当沉默 Nrf2 时，C1 抑制细胞焦亡的积极作用被抑制。特别是，细胞焦亡相关蛋白（包括 NLRP3、GSDMD 和 caspase-1）和促炎分子（包括 IL-1 和 IL-18）的产生增加。总之，这些发现表明 C1 可以通过激活 Nrf2 通路抑制细胞焦亡来减轻 AD 样病理学。我们相信，这项研究可为 AD 的预防和治疗提供新的策略。
