Wang Guangming, Hu Hongkang, Liu Junbin, Fei Xiaowei, Dou Yanan, Wang Li, Ying Lin, Hu Guohan, Zhang Danfeng, Jiang Lei, Wei Jialiang
Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China.
Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China.
Cell Mol Neurobiol. 2025 May 20;45(1):47. doi: 10.1007/s10571-025-01566-w.
There are few effective pharmacological interventions for intracerebral hemorrhage (ICH). Atorvastatin (Ato) has been shown to exert a substantial protective effect on ischemic stroke and is effective in alleviating neuroinflammation. Lipocalin-2 (LCN2), an important inflammation-regulating protein, has been demonstrated to play pivotal roles in post-ICH neuroinflammation. However, the exact role of Ato and whether LCN2 is involved after ICH remain largely unknown. In the current study, the BV2 (microglia) cell line, which was transfected with or without LCN2 for overexpression/interference, was co-cultured with primary cultured neurons and received blood infusion from C57BL/6 mice in vitro. For the in vivo study, atorvastatin was injected peritoneally into an ICH mouse model, and LCN2 specific knockout using the flox/cre system was performed in mice for mechanism study. Behavioral tests were conducted before ICH and on days 1, 3, and 7 post-ICH, and the brains and cultured cells were collected for protein, histological, and morphological studies. Our results showed that atorvastatin treatment alleviates neural damage and promotes neurological outcomes after ICH. Moreover, M1 activation and pro-inflammatory polarization are inhibited by atorvastatin. In both in vivo and in vitro models, the upregulation of LCN2 after ICH is substantially inhibited by atorvastatin. Studies on LCN2 transgenic mice and LCN2 overexpression/interference cells demonstrated that the suppression of macrophage/microglia (M/M) LCN2 participates in atorvastatin-mediated anti-neuroinflammation and neural protection effects. Therefore, our study suggests that atorvastatin treatment attenuates M/M-related neuroinflammation and protects neural recovery by down-regulating LCN2 after ICH. This study identified a potential novel therapeutic target for ICH treatment.
对于脑出血（ICH），几乎没有有效的药物干预措施。阿托伐他汀（Ato）已被证明对缺血性中风具有显著的保护作用，并且在减轻神经炎症方面有效。脂质运载蛋白2（LCN2）是一种重要的炎症调节蛋白，已被证明在脑出血后的神经炎症中起关键作用。然而，阿托伐他汀的确切作用以及脑出血后LCN2是否参与其中在很大程度上仍不清楚。在本研究中，将转染有或未转染LCN2以进行过表达/干扰的BV2（小胶质细胞）细胞系与原代培养的神经元共培养，并在体外接受来自C57BL/6小鼠的血液灌注。对于体内研究，将阿托伐他汀腹腔注射到脑出血小鼠模型中，并使用flox/cre系统在小鼠中进行LCN2特异性敲除以进行机制研究。在脑出血前以及脑出血后第1、3和7天进行行为测试，并收集大脑和培养的细胞用于蛋白质、组织学和形态学研究。我们的结果表明，阿托伐他汀治疗可减轻脑出血后的神经损伤并促进神经功能恢复。此外，阿托伐他汀可抑制M1激活和促炎极化。在体内和体外模型中，脑出血后LCN2的上调均被阿托伐他汀显著抑制。对LCN2转基因小鼠和LCN2过表达/干扰细胞的研究表明，巨噬细胞/小胶质细胞（M/M）LCN2的抑制参与了阿托伐他汀介导的抗神经炎症和神经保护作用。因此，我们的研究表明，阿托伐他汀治疗可通过下调脑出血后的LCN2来减轻与M/M相关的神经炎症并保护神经恢复。本研究确定了一种潜在的脑出血治疗新靶点。
