Astragaloside IV promotes cerebral tissue restoration through activating AMPK- mediated microglia polarization in ischemic stroke rats

• Published in: Journal of ethnopharmacology 2024-11, Vol.334, p.118532, Article 118532
• Main Authors: Li, Ming-cong, Jia, Jing-ting, Wang, Yu-xuan, Zhuang, Yu-ming, Wang, Han-yu, Lin, Zi-yue, Lu, Yun, Li, Man-zhong, Wang, Zhan-jing, Zhao, Hui
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Astragaloside IV; Brain - drug effects; Brain - pathology; Cell Line; Disease Models, Animal; Glycolytic key proteins; Infarction, Middle Cerebral Artery - drug therapy; Ischemic stroke; Ischemic Stroke - drug therapy; Male; Microglia - drug effects; Microglia polarization; Neuroprotective Agents - pharmacology; Rats; Rats, Sprague-Dawley; Saponins - pharmacology; Saponins - therapeutic use; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Triterpenes - pharmacology; Triterpenes - therapeutic use
• ISSN: 0378-8741; 1872-7573; 1872-7573
• DOI: 10.1016/j.jep.2024.118532

Astragaloside IV (AS), a key active ingredient obtained from Chinese herb Astragalus mongholicus Bunge, exerts potent neuroprotective and anti-inflammatory effects for treating neurodegenerative diseases. However, mechanisms of AS on improvement of ischemic brain tissue repair remain unclear. This research aims at using magnetic resonance imaging (MRI) to noninvasively determine whether AS facilitates brain tissue repair, and investigating whether AS exerts brain remodeling through adenosine monophosphate-activated protein kinase (AMPK) metabolic signaling regulating key glycolytic enzymes and energy transporters, thereby impacting microglia polarization. Ischemic stroke model in male Sprague–Dawley rats were induced through permanent occlusion of the middle cerebral artery (MCAO). Infarct volume, the alterations of brain microstructure and nerve fibers reorganization were examined by multi-parametric MRI. The pathological damages of myelinated axons and microglia polarization surrounding infarct tissue were detected using pathological techniques. Furthermore, M1/M2 microglia polarization associated protein, glycolytic rate-limiting enzymes, energy transporters and AMPK/mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) signal were examined both in ischemic stroke rats and BV2 microglia treated with lipopolysaccharide (LPS) + interferon-γ (IFN-γ) by western blotting. MRI revealed that AS obviously decreased infarct volume, relieved brain microstructure damage and improved nerve fibers reorganization in ischemic stroke rats. Histological tests supported MRI findings. Notably, AS promoted microglia M2 and reduced M1 polarization, induced the AMPK activation accompanied with decreased levels of phosphorylated mTOR and HIF-1α. Moreover, AS suppressed the expression of glycolytic rate-limiting enzymes and energy transporters in ischemic stroke rats and BV2 microglia. In contrast, these beneficial effects were greatly blocked by AMPK inhibitor compound C. Overall, these results collectively suggested that AS facilitated tissue remodeling that may be partially through modulating polarization of microglia in AMPK- dependent metabolic pathways after ischemic stroke. [Display omitted] •Astragaloside IV promotes cerebral tissue restoration after ischemic stroke detected by MRI.•Astragaloside IV promotes microglia M2 polarization benefiting ischemic tissue rehabilitation.•Astragaloside IV regulates microglia phenotype polarization through AMPK-m