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Rapamycin Alleviates Neuronal Injury and Modulates Microglial Activation After Cerebral Ischemia

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Abstract

Neurons and microglia are sensitive to cerebral microcirculation and their responses play a crucial part in the pathological processes, while they are also the main target cells of many drugs used to treat brain diseases. Rapamycin exhibits beneficial effects in many diseases; however, whether it can affect neuronal injury or alter the microglial activation after global cerebral ischemia remains unclear. In this study, we performed global cerebral ischemia combined with rapamycin treatment in CX3CR1GFP/+ mice and explored the effects of rapamycin on neuronal deficit and microglial activation. Our results showed that rapamycin reduced neuronal loss, neurodegeneration, and ultrastructural damage after ischemia by histological staining and transmission electron microscopy (TEM). Interestingly, rapamycin suppressed de-ramification and proliferation of microglia and reduced the density of microglia. Immunofluorescence staining indicated that rapamycin skewed microglial polarization toward an anti-inflammatory state. Furthermore, rapamycin as well suppressed the activation of astrocytes. Meanwhile, quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed a significant reduction of pro-inflammatory factors as well as an elevation of anti-inflammatory factors upon rapamycin treatment. As a result of these effects, behavioral tests showed that rapamycin significantly alleviated the brain injury after stroke. Together, our study suggested that rapamycin attenuated neuronal injury, altered microglial activation state, and provided a more beneficial immune microenvironment for the brain, which could be used as a promising therapeutic approach to treat ischemic cerebrovascular diseases.

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Data Availability

The data supporting the findings of this article are available from the corresponding author on reasonable request.

Abbreviations

TEM:

Transmission electron microscopy

qRT-PCR:

Quantitative real-time polymerase chain reaction

CNS:

Central nervous system

MCAO:

Middle cerebral artery occlusion

BCAL:

Bilateral common carotid artery ligation

GFP:

Green fluorescent protein

BCCA:

Bilateral common carotid arteries

CBF:

Cerebral blood flow

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

FJC:

Fluoro-Jade C

BrdU:

Bromodeoxyuridine

ANOVA:

Analysis of variance

SEM:

Standard error of the mean

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Acknowledgements

We thank the Core Facility of School of Life Sciences, Lanzhou University and Cuiying Biomedical Research Center, Lanzhou University Second Hospital for excellent technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China [grant number 81771324], and Fundamental Research Funds for the Central Universities [grant number lzujbky-2022–38].

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Authors and Affiliations

  1. Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, China

    Yue Zhang, Donghai Li, Hao Gao, Haiyu Zhao, Shengxiang Zhang & Ting Li

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Yue Zhang

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  1. Yue Zhang
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  2. Donghai Li
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  3. Hao Gao
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  4. Haiyu Zhao
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  6. Ting Li
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Contributions

In this study, YZ, TL and SXZ designed the research plan. YZ, DHL, and HG performed the experiment. YZ analyzed the data. YZ, HG, HYZ, SXZ, and TL wrote the manuscript. All authors agreed with the submitted version of this manuscript.

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Correspondence to Shengxiang Zhang or Ting Li.

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All experimental procedures and protocols in the study were performed in line with the regulations of the Ethics Committee of Lanzhou University and National Research Council’s Guide for the Care and Use of Laboratory Animals.

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Zhang, Y., Li, D., Gao, H. et al. Rapamycin Alleviates Neuronal Injury and Modulates Microglial Activation After Cerebral Ischemia. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-023-03904-9

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