Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China; Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China; Department of Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, Fujian, China.
Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China; Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
J Ethnopharmacol. 2025 Jan 30;337(Pt 1):118758. doi: 10.1016/j.jep.2024.118758. Epub 2024 Sep 1.
Increasing evidence suggests that ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, may play a substantial role in the traumatic brain injury (TBI) pathophysiology. 3-n-butylphthalide (NBP), a compound extracted from the seeds of Apium graveolens Linn (Chinese celery) and used in China to treat ischemic stroke, has demonstrated encouraging anti-reactive oxygen species (ROS) effects. Ascertaining whether NBP can inhibit ferroptosis and its mechanism could potentially expand its use in models of neurological injury and neurodegenerative diseases.
In this study, we used erastin-induced in vitro ferroptosis models (HT22 cells, hippocampal slices, and primary neurons) and an in vivo controlled cortical impact mouse model. Our study revealed that NBP administration mitigated erastin-induced death in HT-22 cells and decreased ROS levels, lipid peroxidation, and mitochondrial superoxide indicators, resulting in mitochondrial protection. Moreover, the ability of NBP to inhibit ferroptosis was confirmed in organotypic hippocampal slice cultures and a TBI mouse model. NBP rescued neurons, inhibited microglial activation, and reduced iron levels in the brain tissue. The protective effect of NBP can be partly attributed to the inhibition of the AHR-CYP1B1 axis, as evidenced by RNA-seq and CYP1B1 overexpression/inhibition experiments in HT22 cells and primary neurons.
Our study underscores that NBP inhibition of the AHR-CYP1B1 axis reduces ferroptosis in neuronal damage and ameliorates brain injury.
越来越多的证据表明，铁依赖性细胞死亡形式铁死亡，其特征为脂质过氧化，可能在创伤性脑损伤（TBI）发病机制中起重要作用。3-正丁基苯酞（NBP），一种从 Apium graveolens Linn（中国芹菜）种子中提取的化合物，在中国用于治疗缺血性中风，已显示出令人鼓舞的抗活性氧（ROS）作用。确定 NBP 是否可以抑制铁死亡及其机制可能会扩大其在神经损伤和神经退行性疾病模型中的应用。
在这项研究中，我们使用了依拉司琼诱导的体外铁死亡模型（HT22 细胞、海马切片和原代神经元）和体内皮质撞击控制小鼠模型。我们的研究表明，NBP 给药减轻了 HT-22 细胞中依拉司琼诱导的死亡，并降低了 ROS 水平、脂质过氧化和线粒体超氧化物指标，从而实现了线粒体保护。此外，在器官型海马切片培养物和 TBI 小鼠模型中证实了 NBP 抑制铁死亡的能力。NBP 挽救了神经元，抑制了小胶质细胞激活，并降低了脑组织中的铁水平。NBP 的保护作用部分归因于 AHR-CYP1B1 轴的抑制，这在 HT22 细胞和原代神经元中的 RNA-seq 和 CYP1B1 过表达/抑制实验中得到了证实。
我们的研究强调，NBP 抑制 AHR-CYP1B1 轴可减少神经元损伤中的铁死亡，并改善脑损伤。
