Department of Neurology, Center for Cognitive Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou 350001, China; Institute of Clinical Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou 350001, China; Hong Kong Baptist University, Hong Kong 999077, China.
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Phytomedicine. 2023 Oct;119:154993. doi: 10.1016/j.phymed.2023.154993. Epub 2023 Jul 23.
Ferroptosis playsa crucial role in the development of dementia and dendrobine (Den)possesseshypoglycemic and neuroprotective effects. However, the character of ferroptosis in diabetic encephalopathy (DE) and Den's therapeutic effect remains unclear.
This study aimed to verify the effects of Den on ferroptosis in treating DE and underlying mechanisms.
Den's therapeutic effect was assessed in db/db mice and advanced glycation end products (AGEs)-induced HT22 cells.
After oral administration with Den orMetformin for 8-week, behavioral tests were used to assess cognitive capacity. Then, biochemical analysis was preformed to detect glucose and lipid metabolism levels; histological analysis and transmission electron microscope were applied to evaluate pathological injuries. Meanwhile, EdU staining and flow cytometry were applied to test cell apoptosis. Furthermore, mitochondrial dynamics, iron transport, and Nrf2/GPX4 axis related proteins were detected by western blot or immunofluorescence.
Our results demonstrated that Den remarkably alleviated glucose and lipid metabolism disorders, as well as ameliorated mnemonic deficits of db/db mice. Meanwhile, Den could protect AGEs-induced HT22 cells from death and apoptosis. In addition, we noted that Den inhibited lipid peroxidation by restoring mitochondrial function and reducing reactive oxygen species production. Furthermore, ferroptosis was proven to exist in db/db mice brain and Den could inhibit it via activating Nrf2/GPX4 axis.
These findings indicated that Den could rescue cognitive dysfunction in DE by inhibiting ferroptosis via activating Nrf2/GPX4 axis.
铁死亡在痴呆症的发展中起着关键作用，而冬凌草甲素（Den）具有降血糖和神经保护作用。然而，糖尿病性脑病（DE）中存在铁死亡的特征以及 Den 的治疗效果仍不清楚。
本研究旨在验证 Den 治疗 DE 中铁死亡的作用及其潜在机制。
在 db/db 小鼠和晚期糖基化终产物（AGEs）诱导的 HT22 细胞中评估 Den 的治疗效果。
db/db 小鼠经口给予 Den 或二甲双胍 8 周后，进行行为学测试以评估认知能力。然后，进行生化分析以检测葡萄糖和脂质代谢水平；进行组织学分析和透射电镜检查以评估病理损伤。同时，通过 EdU 染色和流式细胞术检测细胞凋亡。此外，通过 Western blot 或免疫荧光检测线粒体动力学、铁转运和 Nrf2/GPX4 轴相关蛋白。
我们的结果表明，Den 显著改善了 db/db 小鼠的葡萄糖和脂质代谢紊乱，并改善了其记忆缺陷。同时，Den 可保护 AGEs 诱导的 HT22 细胞免于死亡和凋亡。此外，我们注意到 Den 通过恢复线粒体功能和减少活性氧的产生来抑制脂质过氧化。此外，铁死亡在 db/db 小鼠大脑中存在，Den 可通过激活 Nrf2/GPX4 轴来抑制其发生。
这些发现表明，Den 通过激活 Nrf2/GPX4 轴抑制铁死亡来挽救 DE 中的认知功能障碍。
