Won Jun Pil, Yoon Han Jun, Lee Hyuk Gyoon, Seo Han Geuk
Department of Food Science and Biotechnology of Animal Resources, College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea.
Department of Food Science and Biotechnology of Animal Resources, College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea.
Eur J Pharmacol. 2024 Dec 15;985:177104. doi: 10.1016/j.ejphar.2024.177104. Epub 2024 Nov 10.
Excitatory neurotransmitter-induced neuronal ferroptosis has been implicated in multiple neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although there are several reports pertaining to the pharmacological activities of biochanin A, the effects of this isoflavone on excitotoxicity-triggered neuronal ferroptosis remain unclear. In this study, we demonstrate that biochanin A inhibits ferroptosis of mouse hippocampal neurons induced by glutamate or the glutamate analog, kainic acid. Biochanin A significantly inhibited accumulation of intracellular iron and lipid peroxidation in glutamate- or kainic acid-treated mouse hippocampal neurons. Furthermore, biochanin A regulated the level of glutathione peroxidase 4, a master regulator of ferroptosis, by modulating its autophagy-dependent degradation. We observed that biochanin A reduced the glutamate-induced accumulation of intracellular iron by regulating expression of iron metabolism-related proteins including ferroportin-1, divalent metal transferase 1, and transferrin receptor 1. Taken together, these results indicate that biochanin A effectively inhibits hippocampal neuronal death triggered by glutamate or kainic acid. Our study is the first to report that biochanin A has therapeutic potential for the treatment of diseases associated with hippocampal neuronal death, particularly ferroptosis induced by excitatory neurotransmitter.
兴奋性神经递质诱导的神经元铁死亡与多种神经退行性疾病有关，如阿尔茨海默病和帕金森病。尽管有几篇关于生物活性成分A药理活性的报道，但这种异黄酮对兴奋性毒性引发的神经元铁死亡的影响仍不清楚。在本研究中，我们证明生物活性成分A可抑制由谷氨酸或谷氨酸类似物红藻氨酸诱导的小鼠海马神经元铁死亡。生物活性成分A显著抑制谷氨酸或红藻氨酸处理的小鼠海马神经元内铁的积累和脂质过氧化。此外，生物活性成分A通过调节其自噬依赖性降解来调节铁死亡的主要调节因子谷胱甘肽过氧化物酶4的水平。我们观察到生物活性成分A通过调节铁代谢相关蛋白（包括铁转运蛋白1、二价金属转运体1和转铁蛋白受体1）的表达，减少谷氨酸诱导的细胞内铁积累。综上所述，这些结果表明生物活性成分A能有效抑制谷氨酸或红藻氨酸引发的海马神经元死亡。我们的研究首次报道生物活性成分A对与海马神经元死亡相关的疾病，特别是兴奋性神经递质诱导的铁死亡具有治疗潜力。
