Hydroxysafflor yellow A attenuates the blood-brain barrier dysfunction and neuroinflammation through anti-inflammatory microglial polarization after intracerebral hemorrhage

Fei Zheng; Xiaohang Guo; Qiuju Yan; Yaya Zhou; En Hu; Haonan Zhu; Menghan Cheng; Zhe Yu; Mingrui Hu; Ruoqi Ding; Haigang Li; Wei Zhang; Tao Tang; Yang Wang; Teng Li; Changqing Deng

doi:10.1016/j.neuropharm.2025.110576

Hydroxysafflor yellow A attenuates the blood-brain barrier dysfunction and neuroinflammation through anti-inflammatory microglial polarization after intracerebral hemorrhage

Neuropharmacology. 2025 Jun 24:278:110576. doi: 10.1016/j.neuropharm.2025.110576. Online ahead of print.

Authors

Fei Zheng¹, Xiaohang Guo², Qiuju Yan³, Yaya Zhou⁴, En Hu⁵, Haonan Zhu³, Menghan Cheng³, Zhe Yu³, Mingrui Hu³, Ruoqi Ding³, Haigang Li⁶, Wei Zhang¹, Tao Tang⁵, Yang Wang⁵, Teng Li⁷, Changqing Deng⁸

Affiliations

¹ The College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China.
² School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, PR China.
³ Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
⁴ Department of Parasitology, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China.
⁵ Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Xiangya Hospital, Central South University, Jiangxi, Nanchang, 330004, PR China.
⁶ Hunan key laboratory of the research and development of novel pharmaceutical preparations, Changsha Medical University, Changsha, Hunan, 410219, PR China.
⁷ Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Xiangya Hospital, Central South University, Jiangxi, Nanchang, 330004, PR China. Electronic address: litengxiangya@csu.edu.cn.
⁸ The College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China. Electronic address: dchangq@hnucm.edu.cn.

PMID: 40571121
DOI: 10.1016/j.neuropharm.2025.110576

Abstract

The destruction of the blood-brain barrier (BBB) is the most common life-threatening event of intracerebral hemorrhage (ICH). Balancing microglia polarization is a prospective therapeutic strategy for BBB injury. This study aims to explore the neuroprotective effects and the underlying mechanisms of Hydroxysafflor yellow A (HSYA) from the perspective of BBB disruption and neuroinflammation. ICH was induced by intracerebral injection of collagenase Ⅶ in C57BL/6J male mice, and HSYA was injected through the tail vein for three days. We established three oral concentrations for HSYA and found that the administration of HSYA (20 mg/kg/d) significantly improved the neurological deficits of ICH mice and reversed the histopathological damage of the brain. Using IgG and Evans Blue staining, we demonstrated that HSYA prominently facilitated the BBB repair after ICH with no bleeding risk. HSYA greatly enhanced the expression of tight junction proteins (ZO-1, occludin, and claudin-5) but decreased MMP9. HSYA also significantly reduced the CD68⁺ microglia with pro-inflammation mediators (IL-1β, IL-6, TNF-α, iNOS, HO-1, and COX2) and increased the Arg-1⁺ microglia with anti-inflammation mediators (IL-10, and TGF-β). We identified the PI3K/Akt signaling pathway through database mining and bioinformatics analysis and verified the activation of PI3K/Akt by HSYA intervention. Further, employing the PI3K-specific antagonist LY294002 confirmed that the pre-administration of LY294002 mostly negated the neuroprotective effects of HSYA. HSYA activates the PI3K/Akt/mTOR signaling pathway, balancing microglial polarization and improving BBB integrity, highlighting its potential to be an effective drug option for ICH treatment.

Keywords: Blood-brain barrier; Hydroxysafflor yellow A; Intracerebral hemorrhage; Microglial polarization; Neuroinflammation; PI3K/Akt signaling pathway.