Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation

Nannan Liu; Chengdi Liu; Yujiao Yang; Guodong Ma; Guangyi Wei; Shan Liu; Linglei Kong; Guanhua Du

doi:10.1016/j.phrs.2021.105650

Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation

Pharmacol Res. 2021 Jul:169:105650. doi: 10.1016/j.phrs.2021.105650. Epub 2021 May 5.

Authors

Nannan Liu¹, Chengdi Liu², Yujiao Yang³, Guodong Ma², Guangyi Wei¹, Shan Liu¹, Linglei Kong⁴, Guanhua Du⁵

Affiliations

¹ College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
² Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
³ Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China; School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
⁴ Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China. Electronic address: konglinglei@imm.ac.cn.
⁵ College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China. Electronic address: dugh@imm.ac.cn.

PMID: 33964468
DOI: 10.1016/j.phrs.2021.105650

Abstract

Stroke is one of the leading causes of death worldwide. Hemorrhagic transformation (HT) is a common serious complication of ischemic stroke (IS) and is related to poor prognosis. Hyperglycemia after stroke is associated with the occurrence of HT and seriously affects the clinical treatment of stroke. Our previous experiments demonstrated that the Xiao-Xu-Ming decoction effective components group (XXMD), which is a Chinese medicine formula reconstituted by active ingredients, has multiple pharmacological effects in the treatment of IS. However, the effects of XXMD on HT after IS remain unclear. Thus, we investigated the preventive effects of XXMD on hyperglycemia-induced HT and further explored the underlying mechanism. Acute hyperglycemia combined with the electrocoagulation cerebral ischemia model was used to establish the HT model. XXMD (37.5, 75, 150 mg/kg/d) was given by gavage for 5 days. Network pharmacology was used to predict potential targets and pathways of XXMD in HT occurrence, and further studies confirmed the related targets. The results showed that hyperglycemia aggravated neurological deficits and blood-brain barrier (BBB) disruption, leading to intracerebral hemorrhage. Pretreatment with XXMD improved neurological function and BBB integrity and inhibited HT occurrence. Network pharmacology revealed that AGE-RAGE-mediated neuroinflammation may be associated with hyperglycemia-induced HT. Further studies confirmed that hyperglycemia activated the AGE-RAGE signaling pathway, increased the expression of HMGB1, TLR4 and p-p65, and induced the release of inflammatory factors and neutrophil infiltration, leading to HT. XXMD could inhibit AGE-RAGE-mediated neuroinflammation. These findings indicated that pretreatment with XXMD alleviated hyperglycemia-induced HT, which may be associated with the inhibition of AGE-RAGE-mediated neuroinflammation. Therefore, XXMD may be a potential therapeutic drug for HT.

Keywords: AGE-RAGE; Blood-brain barrier; Hemorrhagic transformation; Hyperglycemia; Ischemic stroke; Xiao-Xu-Ming decoction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Ischemia / complications
Cerebral Hemorrhage / drug therapy
Cerebral Hemorrhage / prevention & control*
Drugs, Chinese Herbal / therapeutic use*
Hyperglycemia / complications
Hyperglycemia / drug therapy*
Male
Network Pharmacology / methods
Neuroinflammatory Diseases / drug therapy
Neuroinflammatory Diseases / prevention & control*
Rats
Rats, Sprague-Dawley
Receptor for Advanced Glycation End Products / metabolism*
Receptor for Advanced Glycation End Products / physiology

Substances

Drugs, Chinese Herbal
Receptor for Advanced Glycation End Products
xiao-xu-ming