Naotaifang formula attenuates OGD/R-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through BMP6/SMADs signaling pathway

Jun Liao; Mengzhen Wei; Jianjun Wang; Jinsong Zeng; Danhong Liu; Qiusi Du; Jinwen Ge; Zhigang Mei

doi:10.1016/j.biopha.2023.115465

Naotaifang formula attenuates OGD/R-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through BMP6/SMADs signaling pathway

Biomed Pharmacother. 2023 Nov:167:115465. doi: 10.1016/j.biopha.2023.115465. Epub 2023 Sep 15.

Authors

Jun Liao¹, Mengzhen Wei², Jianjun Wang², Jinsong Zeng³, Danhong Liu², Qiusi Du², Jinwen Ge⁴, Zhigang Mei⁵

Affiliations

¹ Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Vascular Biology Laboratory, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China. Electronic address: liaojun@hnucm.edu.cn.
² Vascular Biology Laboratory, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
³ Neurosurgery Department, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
⁴ Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Academy of Traditional Chinese Medicine, Changsha, Hunan 410031, China. Electronic address: 001267@hnucm.edu.cn.
⁵ Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China. Electronic address: meizhigang@hnucm.edu.cn.

PMID: 37713988
DOI: 10.1016/j.biopha.2023.115465

Abstract

Background: Cerebral ischemia-reperfusion injury (CIRI), a subsequent injury caused by thrombolytic reperfusion post ischemic stroke (IS). Naotaifang (NTF) formula, a novel traditional Chinese medicine (TCM) remedy against IS, was shown to exert beneficial effects in inhibiting inflammation and inhibiting lipid peroxide synthesis in our previous research.

Purpose: This study aimed to further explore the role of NTF in attenuating oxygen-glucose deprivation//reoxygenation (OGD/R)-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through the bone morphogenetic protein 6（BMP6）/SMADs signaling pathway.

Methods: BV2 microglia were used to establish an OGD/R model. The effects of NTF on inflammation and ferroptosis in OGD/R-injured BV2 cells were separately detected by immunofluorescence assay, fluorescent probe, DCFH-DA flow cytometry, enzyme-linked immunosorbent assay, and western-blot.

Results: The present results revealed that the M1 phenotype of microglia promoted the secretion of pro-inflammatory cytokines and aggravated ferroptosis and brain damage following OGD/R. However, an inhibitor of BMP6, LND-193189, reversed the aforementioned effects. Similarly, NTF promoted the shift of microglia from M1 to M2. Besides, NTF treatment effectively inhibited the expression of hepcidin, BMP6, SMADs and promoted the expression of ferroportin (FPN, SLC40A1) and γ-L-glutamyl-L-cysteinylglycine (glutathione or GSH) peroxidase 4 (GPX4).

Conclusion: Microglial M1/M2 polarization plays a pivotal role in inflammation and ferroptosis during OGD/R. The BMP6/SMADs signaling pathway is a potential therapeutical target of inflammation and ferroptosis induced by the transformation of microglia. Moreover, NTF could alleviate inflammation and ferroptosis through the BMP6/SMADs signaling pathway in OGD/R-injured microglia.

Keywords: BMP6/SMADs; Ferroptosis; Microglia; Naotaifang; Neuroinflammation; OGD/R.