青蒿素通过激活 Nrf2 抑制 T2DM 小鼠海马神经元铁死亡改善认知功能下降。
Artemisinin ameliorates cognitive decline by inhibiting hippocampal neuronal ferroptosis via Nrf2 activation in T2DM mice.
机构信息
Institute of Anesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
Department of Nuclear Medicine, Affiliated Hospital of Xiangnan University, No. 25 Renmin West Road, Beihu District, Chenzhou, 423001, Hunan, China.
出版信息
Mol Med. 2024 Mar 7;30(1):35. doi: 10.1186/s10020-024-00797-9.
BACKGROUND
Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region.
METHODS
STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests. Hippocampal ROS, MDA, GSH, and Fe contents were detected by assay kits. Nrf2, p-Nrf2, HO-1, and GPX4 proteins in hippocampal CA1 were assessed by Western blotting. Hippocampal neuron injury and mitochondrial morphology were observed using H&E staining and a transmission electron microscope, respectively.
RESULTS
Artemisinin reversed diabetic cognitive impairments, decreased the concentrations of ROS, MDA and Fe, and increased the levels of p-Nr2, HO-1, GPX4 and GSH. Moreover, artemisinin alleviated neuronal loss and ferroptosis in the hippocampal CA1 region. However, these neuroprotective effects of artemisinin were abolished by Nrf2 inhibitor ML385 and ferroptosis inducer erastin.
CONCLUSION
Artemisinin effectively ameliorates neuropathological changes and learning and memory decline in T2DM mice; the underlying mechanism involves the activation of Nrf2 to inhibit neuronal ferroptosis in the hippocampus.
背景
神经元铁死亡在认知功能障碍的发病机制中起关键作用。本研究探讨了青蒿素是否通过减轻海马 CA1 区神经元铁死亡来保护 2 型糖尿病（T2DM）小鼠免受认知障碍。
方法
用 STZ 诱导 T2DM 小鼠，用青蒿素（40mg/kg，腹腔注射）或青蒿素和 Nrf2 抑制剂 MEL385 或铁死亡诱导剂 erastin 共同处理 4 周。通过 Morris 水迷宫和 Y 迷宫试验测定认知表现。通过试剂盒检测海马 ROS、MDA、GSH 和 Fe 含量。通过 Western blot 测定海马 CA1 中的 Nrf2、p-Nrf2、HO-1 和 GPX4 蛋白。用 H&E 染色和透射电子显微镜观察海马神经元损伤和线粒体形态。
结果
青蒿素逆转了糖尿病认知障碍，降低了 ROS、MDA 和 Fe 的浓度，增加了 p-Nr2、HO-1、GPX4 和 GSH 的水平。此外，青蒿素减轻了海马 CA1 区神经元丢失和铁死亡。然而，Nrf2 抑制剂 ML385 和铁死亡诱导剂 erastin 消除了青蒿素的这些神经保护作用。
结论
青蒿素有效改善了 T2DM 小鼠的神经病理变化和学习记忆下降；其潜在机制涉及激活 Nrf2 抑制海马神经元铁死亡。
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