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Anti-brain Aging Effects of Small Molecule Inhibitor DDQ

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Abstract

The purpose of our study is to determine the protective effects of the newly discovered molecule DDQ (diethyl (3,4-dihydroxyphenethylamino)(quinolin-4-yl) methylphosphonate) against aging in an in vitro, mouse primary hippocampal neurons, HT22 cells, and in vivo, 24-month-old C57BL6/J mice. Using biochemical and molecular methods, we studied the half-life period in the blood and brain, optimized the dose, determined dose-response (using 1, 5, 10, 20, and 50 mg/kg body weight), and measured the levels of blood, skeletal muscle, and brain. Using Morris water maze (cognitive behavior), q-RT-PCR (mRNA and protein levels of longevity genes SIRTUINS), transmission electron microscopy (mitochondrial number and length), and Golgi-Cox staining (dendritic spine number and length) were assessed in 24-month-old C57BL6/J mice. Out of 5 different doses of DDQ, the 20 mg/kg body weight dose showed the strongest protective effects against aging in C57BL6/J mice. The half-life time of DDQ is 20 h in the serum and 12 h in the brain. Our extensive pharmacodynamics analysis revealed high peak levels of DDQ in the skeletal muscle, followed by serum and brain. Using mouse primary hippocampal (HT22) neurons and 24-month-old C57BL6/J mice, we tested the protective effects of DDQ. Interestingly, longevity genes SIRTUINS were upregulated in DDQ-treated HT22 cells, and DDQ-treated aged wild-type mice relative to DDQ-untreated cells and untreated aged control mice. Dendritic spines and the quality of mitochondria were significantly increased in DDQ-treated aged mice. Current study findings, together with our previous study observations, strongly suggest that DDQ has anti-aging effects and warrants further investigations of anti-inflammatory, anti-DNA damage, and telomerase activity studies.

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Funding

The research presented in this article was supported by the National Institutes of Health (NIH) grants AG042178, AG047812, NS105473, AG060767, AG069333, AG066347, and R41 AG060836.

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Authors and Affiliations

  1. Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    Murali Vijayan, Chhanda Bose & P. Hemachandra Reddy

  2. Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  3. Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  4. Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  5. Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  6. Public Health and School of Health Professions, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX, 79430, USA

    P. Hemachandra Reddy

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  1. Murali Vijayan
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  2. Chhanda Bose
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Contributions

P. H. R. and V.M. contributed to the conceptualization and formatting of the article. V.M. performed experiments and analyzed the data. V.M., C.B., and P.H.R. are responsible for writing, original draft preparation, and finalization of the manuscript. P.H.R. is responsible for funding acquisition.

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Correspondence to P. Hemachandra Reddy.

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Conflict of Interest

A patent is pending for the discovery of molecule, DDQ, and we have a minority financial interest with a small business company abSynapTex, LLC, based at Lubbock, TX, USA.

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Vijayan, M., Bose, C. & Reddy, P.H. Anti-brain Aging Effects of Small Molecule Inhibitor DDQ. Mol Neurobiol 58, 3588–3600 (2021). https://doi.org/10.1007/s12035-021-02360-7

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  • DOI: https://doi.org/10.1007/s12035-021-02360-7

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