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Pharmacological Targeting of Mitochondrial Fission and Fusion Alleviates Cognitive Impairment and Brain Pathologies in Pre-diabetic Rats

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Abstract

It has recently been accepted that long-term high-fat diet (HFD) intake is a significant possible cause for prediabetes and cognitive and brain dysfunction through the disruption of brain mitochondrial function and dynamic balance. Although modulation of mitochondrial dynamics by inhibiting fission and promoting fusion has been shown to reduce the morbidity and mortality associated with a variety of chronic diseases, the impact of either pharmacological inhibition of mitochondrial fission (Mdivi-1) or stimulation of fusion (M1) on brain function in HFD-induced prediabetic models has never been studied. Thirty-two male Wistar rats were separated into 2 groups and fed either a normal diet (ND, n = 8) or HFD (n = 24) for 14 weeks. At week 12, HFD-fed rats were divided into 3 subgroups (n = 8/subgroup) and given an intraperitoneal injection of either saline, Mdivi-1 (1.2 mg/kg/day), or M1 (2 mg/kg/day) for 2 weeks. Cognitive function and metabolic parameters were determined toward the end of the protocol. The rats then were euthanized, and the brain was immediately removed in order to evaluate brain mitochondrial function and mitochondrial dynamics. HFD-fed rats experienced prediabetes, evidenced by elevated plasma insulin and the HOMA index, impaired mitochondrial function in the brain, altered dynamic regulation, and cognitive impairment were also found. Mdivi-1 and M1 treatment exerted neuroprotection to a similar extent by improving metabolic parameters, balancing mitochondrial dynamics, and reducing mitochondrial dysfunction, resulting in a gradual increase in cognitive function. Therefore, pharmacological targeting of mitochondrial fission and fusion protected the brain against chronic HFD-induced prediabetes.

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Acknowledgements

We wish to thank Siripong Palee, Thidarat Jaiwongkam, and Sasiwan Kerdphoo for their laboratory assistance.

Funding

This work was supported by the Senior Research Scholar Grant from the National Research Council of Thailand (S.C.C.), the NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand (N.C.), the Chiang Mai University Center of Excellence Award (N.C.), the National Research Council of Thailand, Fundamental Fund 2022, Chiang Mai University (C.M.), and the National Research Council of Thailand (C.M.).

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Authors and Affiliations

  1. Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Chayodom Maneechote, Titikorn Chunchai, Nattayaporn Apaijai, Nipon Chattipakorn & Siriporn C. Chattipakorn

  2. Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand

    Chayodom Maneechote, Titikorn Chunchai, Nattayaporn Apaijai, Nipon Chattipakorn & Siriporn C. Chattipakorn

  3. Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Nattayaporn Apaijai & Nipon Chattipakorn

  4. Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand

    Siriporn C. Chattipakorn

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  1. Chayodom Maneechote
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Contributions

C.M. performed the experiments, analyzed the data, and wrote the manuscript. T.C., N.A. performed the experiments. N.C. designed the study, contributed to the discussion, and edited the manuscript. S.C.C. designed the study, analyzed the data, contributed to the discussion, and edited and finalized the manuscript.

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Correspondence to Siriporn C. Chattipakorn.

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The protocols were approved by the Institutional Animal Care and Use Committee of the Faculty of Medicine, Chiang Mai University, Thailand (Permit No. 34/2561) and were performed at the Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

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Maneechote, C., Chunchai, T., Apaijai, N. et al. Pharmacological Targeting of Mitochondrial Fission and Fusion Alleviates Cognitive Impairment and Brain Pathologies in Pre-diabetic Rats. Mol Neurobiol 59, 3690–3702 (2022). https://doi.org/10.1007/s12035-022-02813-7

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