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TRPM7 Mediates BSCB Disruption After Spinal Cord Injury by Regulating the mTOR/JMJD3 Axis in Rats

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Abstract

After spinal cord injury (SCI), secondary injuries including blood cells infiltration followed by the production of inflammatory mediators are led by blood-spinal cord barrier (BSCB) breakdown. Therefore, preventing BSCB damage could alleviate the secondary injury progresses after SCI. Recently, we reported that transient receptor potential melastatin 7 channel (TRPM7) expression is increased in vascular endothelial cells after injury and thereby mediates BSCB disruption. However, the mechanism by which TRPM7 regulates BSCB disruption has not been examined yet. In current research, we show that TRPM7 mediates BSCB disruption via mammalian target of rapamycin (mTOR) pathway after SCI in rats. After contusion injury at T9 level of spinal cord, mTOR pathway was activated in the endothelial cells of blood vessels and TRPM7 was involved in the activation of mTOR pathway. BSCB disruption, MMP-2/9 activation, and blood cell infiltration after injury were alleviated by rapamycin, a mTOR signaling inhibitor. Rapamycin also conserved the level of tight junction proteins, which were decreased after SCI. Furthermore, mTOR pathway regulated the expression and activation of histone H3K27 demethylase JMJD3, known as a key epigenetic regulator mediating BSCB damage after SCI. In addition, rapamycin inhibited JMJD3 expression, the loss of tight junction molecules, and MMP-2/9 expression in bEnd.3, a brain endothelial cell line, after oxygen-glucose deprivation/reoxygenation. Thus, our results suggest that TRPM7 contributes to the BSCB disruption by regulating JMJD3 expression through the mTOR pathway after SCI.

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Data Availability

All raw data used and analyzed for the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No. NRF-2022R1A2B5B02002106) and by a grant from Kyung Hee University in 2021 (KHU-20210142).

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No. NRF-2022R1A2B5B02002106) and by a grant from Kyung Hee University in 2021 (KHU-20210142).

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Authors and Affiliations

  1. Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea

    Chan Sol Park, Jee Youn Lee & Tae Young Yune

  2. Department of Biomedical Science, Kyung Hee University, Seoul, 02447, Republic of Korea

    Chan Sol Park, Kyung Jin Seo, In Yi Kim & Tae Young Yune

  3. Department of Life Science, Sogang University, Seoul, 04107, Republic of Korea

    Bong Gun Ju

  4. Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea

    Tae Young Yune

  5. Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Korea

    Tae Young Yune

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Chan Sol Park: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing. Jee Youn Lee: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing, Funding acquisition. Bong Gun Ju: Conceptualization, Investigation. Tae Young Yune: Conceptualization, Supervision, Project administration, Fundin g acquisition.

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All animal experiments were performed in accordance with the Guidelines and Policies for Rodent Survival Surgery provided by the Animal Care Committee of the Kyung Hee University (Permission number: KHUASP(SE)-17-059).

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Park, C.S., Lee, J.Y., Seo, K.J. et al. TRPM7 Mediates BSCB Disruption After Spinal Cord Injury by Regulating the mTOR/JMJD3 Axis in Rats. Mol Neurobiol 61, 662–677 (2024). https://doi.org/10.1007/s12035-023-03617-z

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