Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1‐polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway

Author:

Xie Guanfeng1,Liang Yubing1,Gao Wen2,Wu Liya3,Zhang Yan1,Ye Ziming1,Qin Chao1ORCID

Affiliation:

1. Department of Neurology The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China

2. Department of Neurology Liuzhou People's Hospital Liuzhou Guangxi China

3. Department of Neurology The Fourth Affiliated Hospital of Guangxi Medical University/Liuzhou Worker's Hospital Liuzhou Guangxi China

Abstract

AbstractIntracerebral haemorrhage (ICH) is a catastrophic subtype of stroke with severe morbidity and mortality. However, little progress has been made in the subsequent secondary injury. Artesunate, a water‐soluble semi‐synthetic derivative of artemisinin, exhibits remarkable pharmacological effects on anti‐neuroinflammation. However, the effects of artesunate on ICH remain unknown. In the present study, haemoglobin (Hb) treatment in BV2 cell and collagenase type IV intracerebroventricular injection in Sprague–Dawley rats were used to establish in vitro and in vivo ICH models, respectively. For in vivo, the neurological scores, haematoma volume, brain oedema, inflammatory factors and iron deposition were evaluated. Besides, lipopolysaccharide (LPS) was used in in vitro to polarize BV2 cell to M1 phenotype. Cell viability, cellular reactive oxygen species (ROS), Fe2+ concentration, and lipid peroxidation levels, ferroptosis‐associated proteins and mRNA, morphological of mitochondria were measured in vitro. Additionally, the AMP‐activated protein kinase (AMPK)/mammalian/mechanistic target of rapamycin (mTOR) pathway were measured by western blot and immunofluorescence staining. The present in vivo results indicated that artesunate significantly ameliorated neurological deficits, haematoma volume and brain oedema in ICH rats. Besides, artesunate suppressed the M1‐microglia relative inflammatory factors and up‐regulated iron deposition. For in vitro, artesunate significantly selectively decreased the viability of LPS‐stimulated BV2 cell. Furthermore, ROS and lipid peroxidation levels were up‐regulated. And the glutathione peroxidase 4 (GPX4) were silenced via the AMPK/mTORC1 axis. Our finding supports that artesunate ameliorates the ICH secondary injury both in vitro and in vivo by inducing ferroptosis in microglia and further inhibiting inflammation mainly through the AMPK/mTORC1/GPX4 pathway. This finding may provide a novel target for ICH treatment.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Pharmacology,Toxicology,General Medicine

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