Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice

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

doi:10.1007/s12017-007-8010-1

Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice

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

Department of Life Science

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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.

Original language	English
Pages (from-to)	315-323
Number of pages	9
Journal	NeuroMolecular Medicine
Volume	9
Issue number	4
DOIs	https://doi.org/10.1007/s12017-007-8010-1
State	Published - Dec 2007

Bibliographical note

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

Keywords

Middle cerebral artery occlusion
Oxygen and glucose deprivation
Permanent middle cerebral artery occlusion
Reactive oxygen species
Uric acid analogues

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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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author = "Frank Haberman and Tang, {Sung Chun} and Arumugam, {Thiruma V.} and Hyun, {Dong Hoon} and Yu, {Qian Sheng} and Cutler, {Roy G.} and Zhihong Guo and Holloway, {Harold W.} and Greig, {Nigel H.} and Mattson, {Mark P.}",

note = "Funding Information: 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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AU - Cutler, Roy G.

AU - Guo, Zhihong

AU - Holloway, Harold W.

AU - Greig, Nigel H.

AU - Mattson, Mark P.

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AB - 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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Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice

Abstract

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Keywords

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