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<p>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.</p> Graphical Abstract <p>Atorvastatin treatment counteracts M/M-related neuroinflammation, marked by M1 phenotype marker expression and pro-inflammatory cytokines IL-1β and TNF release, and protects neural recovery, marked by facilitated clot reduction, alleviated neural damage and neurologic functional recovery, after ICH via down-regulation M/M LCN2 expression.</p> <p></p>

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Atorvastatin Protects Against the Macrophage/Microglia-Related Neuroinflammation via Inhibiting Lipocalin-2 in Mouse Experimental Intracerebral Hemorrhage Model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月20日

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  • Guangming Wang,
  • Hongkang Hu,
  • Junbin Liu,
  • Xiaowei Fei,
  • Yanan Dou,
  • Li Wang,
  • Lin Ying,
  • Guohan Hu,
  • Danfeng Zhang,
  • Lei Jiang,
  • Jialiang Wei

摘要

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.

Graphical Abstract

Atorvastatin treatment counteracts M/M-related neuroinflammation, marked by M1 phenotype marker expression and pro-inflammatory cytokines IL-1β and TNF release, and protects neural recovery, marked by facilitated clot reduction, alleviated neural damage and neurologic functional recovery, after ICH via down-regulation M/M LCN2 expression.