Scutellarin Modulates Astrocyte-Microglia-Neuron Crosstalk to Mitigate Neuroinflammation and Apoptosis in Cerebral Ischemia

Haolun Chen; Zhaoda Duan; Qiuye Jia; Xiaolina Zhang; Dongyao Xu; Liyang Zheng; Zhi Qi; Yujia Yang; Li Yang; Chunyun Wu

doi:10.1007/s12035-025-04933-2

Scutellarin Modulates Astrocyte-Microglia-Neuron Crosstalk to Mitigate Neuroinflammation and Apoptosis in Cerebral Ischemia

Mol Neurobiol. 2025 Apr 15. doi: 10.1007/s12035-025-04933-2. Online ahead of print.

Authors

Haolun Chen^#^{1

2}, Zhaoda Duan^#^{1

3}, Qiuye Jia^#¹, Xiaolina Zhang^{1

4}, Dongyao Xu¹, Liyang Zheng¹, Zhi Qi^{1

4}, Yujia Yang¹, Li Yang⁵, Chunyun Wu⁶

Affiliations

¹ Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, PR China.
² School of Physical Education, Yunnan Minzu University, Yuehua Street 2929, Kunming, 650500, China.
³ School of Biomedical Engineering Research Institute, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, PR China.
⁴ Department of Pain Management, No.1 Affiliated Hospital, Kunming Medical University, 295 Xichang Road, Kunming, 650101, People's Republic of China.
⁵ Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, PR China. yanglikm@163.com.
⁶ Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, PR China. wuchunyunkm@163.com.

^# Contributed equally.

PMID: 40232642
DOI: 10.1007/s12035-025-04933-2

Abstract

This study investigates whether scutellarin promotes astrocyte polarization in MCAO and OGD models, and its effects on astrocyte-microglia, astrocyte-neuron interactions, and the PI3K-Akt pathway in neuroprotection. We used an experimentally induced cerebral ischemia rat model and OGD-stimulated TNC1 cell model. Using western blot, RT-qPCR and immunofluorescence, we show a noticeable increase in the expression of A2 astrocyte markers and a downregulation of A1 astrocyte markers in activated astrocytes, both in vivo and in vitro. Remarkably, after the treatment of scutellarin, OGD-stimulated TNC1 cells markedly downregulated M1 microglia markers and apoptosis factors in PC12 cells, while upregulating M2 microglia markers and anti-apoptosis factor Bcl2. Therefore, it is suggested that scutellarin can promote the polarization of activated astrocyte from the A1 to the A2 phenotype. Meanwhile, there is indeed a crosstalk between astrocytes-microglia and astrocytes-neurons, and astrocytes treated with scutellarin can promote M2 polarization of microglia and neuronal apoptosis. More importantly, based on the results of transcriptome sequencing, we used TNC1-pik3r1-siRNA cell model and pcDNA3.1 ( +)-pik3r1-TNC1 cell model to investigate the effect of the PI3K-Akt signaling pathway on the polarization of astrocyte and their crosstalk. Scutellarin promotes the A2 polarization, M2 polarization, and anti-apoptosis in astrocyte crosstalk by concomitantly enhancing the PI3K-Akt signaling pathway. This is strongly supported by observations in TNC1 astrocyte in TNC1-pik3r1-siRNA cell model, where the expression of A2 markers was decreased. Conversely, in the pcDNA3.1 ( +)-pik3r1-TNC1 cell model, expression was increased. In light of the above, the PI3K-Akt signaling pathway is considered a potential therapeutic target.

Keywords: Astrocyte polarization; Cross-talk; Microglia; PC12 cells; PI3 K/Akt signaling pathway; Scutellarin.

Abstract

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