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Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage

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Abstract

Hypoglycemia is associated with cognitive dysfunction, but the exact mechanisms have not been elucidated. Our previous study found that severe hypoglycemia could lead to cognitive dysfunction in a type 1 diabetes (T1D) mouse model. Thus, the aim of this study was to further investigate whether the mechanism of severe hypoglycemia leading to cognitive dysfunction is related to oxidative stress-mediated pericyte loss and blood-brain barrier (BBB) leakage. A streptozotocin T1D model (150 mg/kg, one-time intraperitoneal injection), using male C57BL/6J mice, was used to induce hypoglycemia. Brain tissue was extracted to examine for neuronal damage, permeability of BBB was investigated through Evans blue staining and electron microscopy, reactive oxygen species and adenosine triphosphate in brain tissue were assayed, and the functional changes of pericytes were determined. Cognitive function was tested using Morris water maze. Also, an in vitro glucose deprivation model was constructed. The results showed that BBB leakage after hypoglycemia is associated with excessive activation of oxidative stress and mitochondrial dysfunction due to glucose deprivation/reperfusion. Interventions using the mitochondria-targeted antioxidant Mito-TEMPO in both in vivo and in vitro models reduced mitochondrial oxidative stress, decreased pericyte loss and apoptosis, and attenuated BBB leakage and neuronal damage, ultimately leading to improved cognitive function.

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Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge the Public Technology Service Center Fujian Medical University for providing technical support in laser confocal microscopy. Thanks to the support of my family, especially my husband Fu yang, who gave me a lot of encouragement during this study and let me finish the experiment without worries.

Funding

This work was supported by the Fujian Science and Technology Innovation Joint Fund Project (2017Y9060), the Financial Department Special Funds of Fujian Province (2018B041), the Joint Funds for the innovation of science and Technology, Fujian province (2019Y9062), Shanghai Health and Medical Development Foundation (DMRFP_I_03), and the Startup Fund for Scientific Research of Fujian Medical University (2020QH2022).

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  1. Lu Lin and Zhou Chen contributed equally to this work and share the first authorship

Authors and Affiliations

  1. Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China

    Lu Lin, Cuihua Huang, Yubin Wu, Lishan Huang, Lijing Wang, Sujie Ke & Libin Liu

  2. School of Pharmacy, Fujian Medical University, Fuzhou, China

    Zhou Chen

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  1. Lu Lin
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Lu Lin, Zhou Chen, and Cuihua Huang. The first draft of the manuscript was written by Lin Lu, and all authors commented on previous versions of the manuscript. Yubin Wu, Lishan Huang, Lijing Wang, and Sujie Ke participated in the separation experiment. Libin Liu and conceived and designed the study. All authors read and approved the final manuscript.

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Correspondence to Libin Liu.

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The animal study protocol was approved by the Fujian Animal Research Ethics Committee (protocol code FJMU IACUC 2021-0029).

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Lin, L., Chen, Z., Huang, C. et al. Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage. Mol Neurobiol 60, 672–686 (2023). https://doi.org/10.1007/s12035-022-03101-0

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