Danshen-Chuanxiongqin Injection attenuates cerebral ischemic stroke by inhibiting neuroinflammation via the TLR2/ TLR4-MyD88-NF-κB Pathway in tMCAO mice

Xiao-Jing Xu; Jin-Bo Long; Kai-Yu Jin; Li-Bing Chen; Xiao-Yan Lu; Xiao-Hui Fan

doi:10.1016/S1875-5364(21)60083-3

Danshen-Chuanxiongqin Injection attenuates cerebral ischemic stroke by inhibiting neuroinflammation via the TLR2/ TLR4-MyD88-NF-κB Pathway in tMCAO mice

Chin J Nat Med. 2021 Oct;19(10):772-783. doi: 10.1016/S1875-5364(21)60083-3.

Authors

Xiao-Jing Xu¹, Jin-Bo Long¹, Kai-Yu Jin¹, Li-Bing Chen¹, Xiao-Yan Lu², Xiao-Hui Fan³

Affiliations

¹ Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: luxy@zju.edu.cn.
³ Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. Electronic address: fanxh@zju.edu.cn.

PMID: 34688467
DOI: 10.1016/S1875-5364(21)60083-3

Abstract

Danshen-Chuanxiongqin Injection (DCI) is a commonly used traditional Chinese medicine for the treatment of cerebral ischemic stroke in China. However, its underlying mechanisms remain completely understood. The current study was designed to explore the protective mechanisms of DCI against cerebral ischemic stroke through integrating whole-transcriptome sequencing coupled with network pharmacology analysis. First, using a mouse model of cerebral ischemic stroke by transient middle cerebral artery occlusion (tMCAO), we found that DCI (4.10 mL·kg^-1) significantly alleviated cerebral ischemic infarction, neurological deficits, and the pathological injury of hippocampal and cortical neurons in mice. Next, the whole-transcriptome sequencing was performed on brain tissues. The cerebral ischemia disease (CID) network was constructed by integrating transcriptome sequencing data and cerebrovascular disease-related genes. The results showed CID network was imbalanced due to tMCAO, but a recovery regulation was observed after DCI treatment. Pathway analysis of the key genes with recovery efficiency showed that the neuroinflammation signaling pathway was highly enriched, while the TLR2/TLR4-MyD88-NF-κB pathway was predicted to be affected. Consistently, the in vivo validation experiments confirmed that DCI exhibited protective effects against cerebral ischemic stroke by inhibiting neuroinflammation via the TLR2/TLR4-MyD88-NF-κB pathway. More interestingly, DCI markedly suppressed the neutrophils infiltrated into the brain parenchyma via the choroid plexus route and showed anti-neuroinflammation effects. In conclusion, our results provide dependable evidence that inhibiting neuroinflammation via the TLR2/TLR4-MyD88-NF-κB pathway is the main mechanism of DCI against cerebral ischemic stroke in mice.

Keywords: Cerebral ischemic stroke; Choroid plexus; Danshen-Chuanxiongqin Injection; Network pharmacology; Neuroinflammation; Neutrophil.

MeSH terms

Brain Ischemia* / drug therapy
Brain Ischemia* / genetics
Drugs, Chinese Herbal
Humans
Infarction, Middle Cerebral Artery / drug therapy
Infarction, Middle Cerebral Artery / genetics
Ischemic Stroke*
Myeloid Differentiation Factor 88 / genetics
NF-kappa B / genetics
NF-kappa B / metabolism
Stroke* / drug therapy
Stroke* / genetics
Toll-Like Receptor 2
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / metabolism

Substances

Drugs, Chinese Herbal
Myeloid Differentiation Factor 88
NF-kappa B
TLR2 protein, human
TLR4 protein, human
Toll-Like Receptor 2
Toll-Like Receptor 4
shenxiong glucose