Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China.
Department of Neurosurgery, Renmin Hospital of Wuhan University, No. 9 Zhangzhidong Road, Wuchang District, Wuhan, 430072, Hubei Province, China.
Transl Stroke Res. 2024 Feb;15(1):219-237. doi: 10.1007/s12975-022-01122-4. Epub 2023 Jan 12.
Subarachnoid hemorrhage (SAH) is a type of stroke with high morbidity and mortality. Netrin-1 (NTN-1) can alleviate early brain injury (EBI) following SAH by enhancing peroxisome proliferator-activated receptor gamma (PPARγ), which is an important transcriptional factor modulating lipid metabolism. Ferroptosis is a newly discovered type of cell death related to lipid metabolism. However, the specific function of ferroptosis in NTN-1-mediated neuroprotection following SAH is still unclear. This study aimed to evaluate the neuroprotective effects and the possible molecular basis of NTN-1 in SAH-induced EBI by modulating neuronal ferroptosis using the filament perforations model of SAH in mice and the hemin-stimulated neuron injury model in HT22 cells. NTN-1 or a vehicle was administered 2 h following SAH. We examined neuronal death, brain water content, neurological score, and mortality. NTN-1 treatment led to elevated survival probability, greater survival of neurons, and increased neurological score, indicating that NTN-1-inhibited ferroptosis ameliorated neuron death in vivo/in vitro in response to SAH. Furthermore, NTN-1 treatment enhanced the expression of PPARγ, nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4), which are essential regulators of ferroptosis in EBI after SAH. The findings show that NTN-1 improves neurological outcomes in mice and protects neurons from death caused by neuronal ferroptosis. Furthermore, the mechanism underlying NTN-1 neuroprotection is correlated with the inhibition of ferroptosis, attenuating cell death via the PPARγ/Nrf2/GPX4 pathway and coenzyme Q10-ferroptosis suppressor protein 1 (CoQ10-FSP1) pathway.
蛛网膜下腔出血（SAH）是一种发病率和死亡率都很高的中风类型。轴突导向因子 1（NTN-1）可以通过增强过氧化物酶体增殖物激活受体γ（PPARγ）来减轻 SAH 后的早期脑损伤（EBI），PPARγ是调节脂质代谢的重要转录因子。铁死亡是一种与脂质代谢相关的新型细胞死亡方式。然而，铁死亡在 NTN-1 介导的 SAH 后神经保护中的具体作用尚不清楚。本研究旨在通过调节神经元铁死亡，利用 SAH 小鼠的纤维穿孔模型和 HT22 细胞的血红素刺激神经元损伤模型，评估 NTN-1 在 SAH 诱导的 EBI 中的神经保护作用及其可能的分子基础。SAH 后 2 小时给予 NTN-1 或载体。我们检查了神经元死亡、脑含水量、神经评分和死亡率。NTN-1 治疗可提高生存概率，增加神经元存活，并提高神经评分，表明 NTN-1 抑制铁死亡可改善 SAH 后体内/体外神经元死亡。此外，NTN-1 治疗增强了过氧化物酶体增殖物激活受体γ（PPARγ）、核因子红细胞 2 相关因子 2（Nrf2）和谷胱甘肽过氧化物酶 4（GPX4）的表达，这些都是 SAH 后 EBI 中铁死亡的关键调节因子。研究结果表明，NTN-1 改善了 SAH 小鼠的神经预后，保护神经元免受神经元铁死亡引起的死亡。此外，NTN-1 神经保护的机制与铁死亡的抑制有关，通过 PPARγ/Nrf2/GPX4 途径和辅酶 Q10-铁死亡抑制蛋白 1（CoQ10-FSP1）途径减弱细胞死亡。
