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Soluble Neuroprotective Antioxidant Uric Acid Analogs Ameliorate Ischemic Brain Injury in Mice

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Abstract

Uric acid is a major antioxidant in the blood of humans that can protect cultured neurons against oxidative and metabolic insults. However, uric acid has a very low solubility which compromises its potential clinical use for neurodegenerative disorders. Here we describe the synthesis, characterization and preclinical development of neuroprotective methyl- and sulfur-containing analogs of uric acid with increased solubility. In vitro and cell culture screening identified 1,7-dimethyluric acid (mUA2) and 6,8-dithiouric acid (sUA2) as two analogs with high antioxidant and neuroprotective activities. When administered intravenously in mice, uric acid analogs mUA2 and sUA2 lessened damage to the brain and improved functional outcome in an ischemia-reperfusion mouse model of stroke. Analogs sUA2 and mUA2 were also effective in reducing damage to the cerebral cortex when administered up to 4 h after stroke onset in a permanent middle cerebral artery occlusion mouse model. These findings suggest a therapeutic potential for soluble analogs of uric acid in the treatment of stroke and related neurodegenerative conditions.

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Acknowledgments

This work was supported by the National Institute on Aging Intramural Research Program. We thank Mohammed R Mughal for managing the mouse colony.

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Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD, USA

    Frank Haberman, Sung-Chun Tang, Thiruma V. Arumugam, Dong-Hoon Hyun, Qian-Sheng Yu, Roy G. Cutler, Zhihong Guo, Harold W. Holloway, Nigel H. Greig & Mark P. Mattson

  2. Department of Medicinal Chemistry, Israel Institute for Biological Research, Ness Ziona, Israel

    Frank Haberman

  3. Stroke Center, National Taiwan University Hospital, Yun-Lin Branch, Taipei, Taiwan

    Sung-Chun Tang

  4. Department of Neurology, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Sung-Chun Tang

  5. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, TX, 79106, USA

    Thiruma V. Arumugam

  6. Department of Neurosciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mark P. Mattson

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  1. Frank Haberman
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Correspondence to Mark P. Mattson.

Additional information

Frank Haberman, Sung-Chun Tang and Thiruma V. Arumugam contributed equally.

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Haberman, F., Tang, SC., Arumugam, T.V. et al. Soluble Neuroprotective Antioxidant Uric Acid Analogs Ameliorate Ischemic Brain Injury in Mice. Neuromol Med 9, 315–323 (2007). https://doi.org/10.1007/s12017-007-8010-1

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