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Remote Ischemic Post-conditioning Reduces Cognitive Impairment in Rats Following Subarachnoid Hemorrhage: Possible Involvement in STAT3/STAT5 Phosphorylation and Th17/Treg Cell Homeostasis

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Abstract

The inflammatory response following subarachnoid hemorrhage (SAH) may lead to Early Brain Injury and subsequently contribute to poor prognosis such as cognitive impairment in patients. Currently, there is a lack of effective strategies for SAH to ameliorate inflammation and improve cognitive impairment in clinical. This study aims to examine the inhibitory impact of remote ischemic post-conditioning (RIPostC) on the body’s inflammatory response by regulating Th17/Treg cell homeostasis after SAH. The ultimate goal is to search for potential early treatment targets for SAH. The rat SAH models were made by intravascular puncture of the internal carotid artery. The intervention of RIPostC was administered for three consecutive days immediately after successful modeling. Behavioral experiments including the Morris water maze and Y-maze tests were conducted to assess cognitive functions such as spatial memory, working memory, and learning abilities 2 weeks after successful modeling. The ratio of Th17 cells and Treg cells in the blood was detected using flow cytometry. Immunofluorescence was used to observe the infiltration of neutrophils into the brain. Signal transducers and activators of transcription 5 (STAT5) and signal transducers and activators of transcription 3 (STAT3) phosphorylation levels, receptor-related orphan receptor gamma-t (RORγt), and forkhead box protein P3 (Foxp3) levels were detected by Western blot. The levels of anti-inflammatory factors (IL-2, IL-10, IL-5, etc.) and pro-inflammatory factors (IL-6, IL-17, IL-18, TNF-α, IL-14, etc.) in blood were detected using Luminex Liquid Suspension Chip Assay. RIPostC significantly improved the cognitive impairment caused by SAH in rats. The results showed that infiltration of Th17 cells and neutrophils into brain tissue increased after SAH, leading to the release of pro-inflammatory factors (IL-6, IL-17, IL-18, and TNF-α). This response can be inhibited by RIPostC. Additionally, RIPostC facilitates the transfer of Treg from blood to the brain and triggers the release of anti-inflammatory (IL-2, IL-10, and IL-5) factors to suppress the inflammation following SAH. Finally, it was found that RIPostC increased the phosphorylation of STAT5 while decreasing the phosphorylation of STAT3. RIPostC reduces inflammation after SAH by partially balancing Th17/Treg cell homeostasis, which may be related to downregulation of STAT3 and upregulation of STAT5 phosphorylation, which ultimately alleviates cognitive impairment in rats. Targeting Th17/Treg cell homeostasis may be a promising strategy for early SAH treatment.

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Data Availability

Data are available upon reasonable request.

Abbreviations

SAH:

Subarachnoid hemorrhage

RIPostC:

Remote ischemic post-conditioning

STAT:

Signal transducers and activators of transcription

STAT5:

Signal transducers and activators of transcription 5

STAT3:

Signal transducers and activators of transcription 3

RORγt:

Receptor-related orphan receptor gamma-t

Foxp3:

Forkhead box protein P3

IL-2:

Interleukin-2

IL-4:

Interleukin-4

IL-5:

Interleukin-5

IL-6:

Interleukin-6

IL-10:

Interleukin-10

IL-17:

Interleukin-17

IL-18:

Interleukin-18

TNF-α:

Tumor necrosis factor alpha

VEGF:

Vascular endothelial growth factor

JAK:

Janus kinase

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Acknowledgements

Firstly, we would like to thank the Chongqing Key Laboratory for Major Neuropsychiatric Disorders for providing a platform and technical support for the research. Secondly, we would like to express our gratitude to the Experimental Animal Center of Chongqing Medical University for providing us with experimental animals. Finally, we would like to appreciate Dr. Xiaochuan Sun, Director of the Department of Theology and Gynecology of the First Affiliated Hospital of Chongqing Medical University, Dr. Jiru Zhou, Dr. Linna Gu, Dr. Lin Wang, Dr. Zhao Li, Master Yunchuan Cao, and Master Bo Zeng for providing experimental and technical guidance for this study.

Funding

This work was supported partly by grants from the National Natural Science Foundation of China (Grant number 82071332), the Key Project of Chongqing Science and Health Joint Medical Research Project (2020GDRC024), and the Chongqing Natural Science Foundation Joint Fund for Innovation and Development (CSTB2023NSCQ-LZX0041).

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  1. The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China

    Yajun Zhu, Xiaoguo Li, DaoChen Wen, Zichao Huang, Jin Yan, Zhaosi Zhang, Yingwen Wang & Zongduo Guo

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  1. Yajun Zhu
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Contributions

In this article, Yajun Zhu participated in research design, experimental arrangement, data statistics and analysis, and manuscript preparation. Xiaoguo Li participated in the Luminex Liquid Suspension Chip Assay. DaoChen Wen participated in Western blotting. Zichao Haung participated in flow cytometry. Jin Yan, Zhaosi Zhang and Yingwen Wang participated in the construction of the rat SAH model. Zongduo Guo participated in manuscript editing and manuscript review.All authors reviewed the manuscript.

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Zhu, Y., Li, X., Wen, D. et al. Remote Ischemic Post-conditioning Reduces Cognitive Impairment in Rats Following Subarachnoid Hemorrhage: Possible Involvement in STAT3/STAT5 Phosphorylation and Th17/Treg Cell Homeostasis. Transl. Stroke Res. (2024). https://doi.org/10.1007/s12975-024-01235-y

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