School of Food and Biological Engineering, Key Laboratory for Agricultural Products Processing of Anhui Province, Hefei University of Technology, 230601, Hefei, People's Republic of China.
Center of Scientific Research, Anhui Medical University, 230032, Hefei, People's Republic of China.
J Ethnopharmacol. 2024 Oct 5;332:118363. doi: 10.1016/j.jep.2024.118363. Epub 2024 May 17.
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum, a renowned tonic traditional Chinese medicine, is widely recognized for the exceptional activity in soothing nerves and nourishing the brain. It has been extensively employed to alleviate various neurological disorders, notably Parkinson's disease (PD). AIM OF THE STUDY: To appraise the antiparkinsonian effect of GAA, the main bioactive constituent of G. lucidum, and clarify the molecular mechanism through the perspective of ferritinophagy-mediated dopaminergic neuron ferroptosis. MATERIALS AND METHODS: PD mouse and cell models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP), respectively. Cell viability, behavioral tests and immunofluorescence analysis were performed to evaluate the neurotoxicity, motor dysfunction and dopaminergic loss, respectively. Biochemical assay kits were used to determine the levels of iron, lipid reactive oxygen species (ROS), malondialdehyde (MDA), total ROS and glutathione (GSH). Western blot and immunofluorescence were applied to detect the expressions of nuclear receptor co-activator 4 (NCOA4), ferritin heavy chain 1 (FTH1), p62 and LC3B. Additionally, NCOA4-overexpressing plasmid vector was constructed to verify the inhibitory effect of GAA on the neurotoxicity and ferroptosis-related parameters in PD models. RESULTS: GAA significantly mitigated MPP/MPTP-induced neurotoxicity, motor dysfunction and dopaminergic neuron loss (p＜0.01 or p＜0.05). In contrast to MPP/MPTP treatment, GAA treatment decreased the levels of iron, MDA, lipid and total ROS, while increasing the GSH level. GAA also reduced the levels of NCOA4 and LC3B, and enhanced the expressions of FTH1 and p62 in PD models (p＜0.01 or p＜0.05). However, the protective effect of GAA against the neurotoxicity, NCOA4-mediated ferritinophagy and ferroptosis in PD model was abolished by the overexpression of NCOA4 (p＜0.01). CONCLUSION: GAA exerted a protective effect on PD, and this effect was achieved by suppressing dopaminergic neuron ferroptosis through the inhibition of NCOA4-mediated ferritinophagy.
民族药理学相关性：灵芝，一种著名的滋补中药，因其舒缓神经和滋养大脑的出色活性而广为人知。它已被广泛用于缓解各种神经疾病，尤其是帕金森病 (PD)。
研究目的：评估灵芝主要生物活性成分 GAA 的抗帕金森作用，并从铁蛋白自噬介导的多巴胺能神经元铁死亡角度阐明其分子机制。
材料和方法：使用 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 和 1-甲基-4-苯基吡啶 (MPP) 分别建立 PD 小鼠和细胞模型。通过细胞活力、行为测试和免疫荧光分析分别评估神经毒性、运动功能障碍和多巴胺能神经元丢失。生化试剂盒用于测定铁、脂质活性氧 (ROS)、丙二醛 (MDA)、总 ROS 和谷胱甘肽 (GSH) 的水平。Western blot 和免疫荧光用于检测核受体共激活因子 4 (NCOA4)、铁蛋白重链 1 (FTH1)、p62 和 LC3B 的表达。此外，构建了 NCOA4 过表达质粒载体，以验证 GAA 对 PD 模型中神经毒性和铁死亡相关参数的抑制作用。
结果：GAA 显著减轻 MPP/MPTP 诱导的神经毒性、运动功能障碍和多巴胺能神经元丢失 (p＜0.01 或 p＜0.05)。与 MPP/MPTP 处理相比，GAA 处理降低了铁、MDA、脂质和总 ROS 的水平，同时增加了 GSH 水平。GAA 还降低了 NCOA4 和 LC3B 的水平，并增强了 PD 模型中 FTH1 和 p62 的表达 (p＜0.01 或 p＜0.05)。然而，过表达 NCOA4 后，GAA 对 PD 模型中神经毒性、NCOA4 介导的铁蛋白自噬和铁死亡的保护作用被消除 (p＜0.01)。
结论：GAA 对 PD 具有保护作用，这种作用是通过抑制 NCOA4 介导的铁蛋白自噬来抑制多巴胺能神经元铁死亡来实现的。
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