Puerarin mitigates cognitive decline and white matter injury via CD36-Mediated microglial phagocytosis in chronic cerebral hypoperfusion

Qinghua Luo; Fang Li; Xu Liu; Tengfeng Yan; Li Yang; Wenping Zhu; Heqing Zheng; Yan Li; Jianglong Tu; Xingen Zhu

doi:10.1016/j.phymed.2025.156396

Puerarin mitigates cognitive decline and white matter injury via CD36-Mediated microglial phagocytosis in chronic cerebral hypoperfusion

Phytomedicine. 2025 Jan 16:138:156396. doi: 10.1016/j.phymed.2025.156396. Online ahead of print.

Authors

Qinghua Luo¹, Fang Li², Xu Liu³, Tengfeng Yan⁴, Li Yang⁵, Wenping Zhu⁵, Heqing Zheng², Yan Li⁵, Jianglong Tu⁶, Xingen Zhu⁷

Affiliations

¹ Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China; Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China; JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Provincial Key Laboratory of Neurological Diseases, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330000, China.
² Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China; Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi 330000, China; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330000, China.
³ Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China; JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Provincial Key Laboratory of Neurological Diseases, Nanchang University, Nanchang, Jiangxi, China.
⁴ Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China; Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China; JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Provincial Key Laboratory of Neurological Diseases, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330000, China.
⁵ Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China; JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Provincial Key Laboratory of Neurological Diseases, Nanchang University, Nanchang, Jiangxi, China; Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi 330000, China.
⁶ Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China; JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Provincial Key Laboratory of Neurological Diseases, Nanchang University, Nanchang, Jiangxi, China. Electronic address: [email protected].
⁷ Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China; Jiangxi Provincial Key Laboratory of Nervous System Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, China; JXHC Key Laboratory of Neurological Medicine, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Provincial Key Laboratory of Neurological Diseases, Nanchang University, Nanchang, Jiangxi, China; Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi 330000, China. Electronic address: [email protected].

PMID: 39827816
DOI: 10.1016/j.phymed.2025.156396

Abstract

Background: Chronic cerebral hypoperfusion (CCH) contributes significantly to white matter injury (WMI) and cognitive impairment, often leading to vascular dementia (VaD). Inefficient clearance of myelin debris by microglia impedes white matter repair, making microglia-mediated myelin clearance a promising therapeutic strategy for WMI. Puerarin (Pu), an isoflavonoid monomer from Pueraria lobata, is known for its neuroprotective, anti-inflammatory, and immunoregulatory properties. However, its effects and underlying mechanisms in counteracting CCH-induced damage remain unclear. In this study, we aimed to investigate the therapeutic effects and underlying mechanisms of puerarin in a CCH mouse model.

Methods: Right unilateral common carotid artery occlusion (rUCCAO) was used to model CCH in C57BL/6J mice. Puerarin (400 mg/kg/day) was administered intraperitoneally for 10 consecutive days starting immediately post-surgery. Cognitive function was assessed by the Morris Water Maze (MWM) test. WMI, remyelination, neuroinflammation, and microglial phagocytosis were evaluated by western blotting, immunofluorescence staining, RT-PCR, or flow cytometry both in vivo and in vitro.

Results: Puerarin treatment significantly improved cognitive performance and mitigated WMI in rUCCAO mice. These effects were associated with enhanced microglial phagocytosis and remyelination, reduced neuroinflammation, and increased CD36 expression. Additionally, puerarin also increased the levels of IL-10 and phosphorylated STAT3 (p-STAT3) in brain tissues. Notably, IL-10 neutralization reversed these benefits effects by reducing microglial myelin debris uptake, downregulating STAT3 phosphorylation and CD36 expression.

Conclusions: Our findings demonstrate that puerarin has significant therapeutic potential in treating CCH-related cognitive impairments and WMI by modulating CD36-mediated microglial myelin clearance through the IL-10/STAT3 pathway. However, our study was reliant on preclinical animal models, further studies are needed to explore applicability in human subjects.

Keywords: Chronic cerebral hypoperfusion; IL-10/STAT3/CD36 Signaling Pathway; Memory impairment; Microglial phagocytosis; Puerarin; White matter injury.