Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice
Journal
NeuroMolecular Medicine
Journal Volume
9
Journal Issue
4
Pages
315-323
Date Issued
2007
Author(s)
Haberman F.
Arumugam T.V.
Hyun D.-H.
Yu Q.-S.
Cutler R.G.
Guo Z.
Holloway H.W.
Greig N.H.
Mattson M.P.
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. ? Humana Press Inc. 2007.
SDGs
Other Subjects
1,7 dimethyluric acid; 6,8 dithiouric acid; unclassified drug; uric acid derivative; animal cell; animal experiment; animal model; animal tissue; antioxidant activity; article; brain cortex; brain ischemia; cell culture; controlled study; drug mechanism; drug solubility; drug structure; drug synthesis; female; human; human cell; male; middle cerebral artery occlusion; mouse; nerve degeneration; neuroprotection; nonhuman; outcome assessment; priority journal; rat; reperfusion; stroke; Animals; Antioxidants; Blood Flow Velocity; Brain Injuries; Brain Ischemia; Cell Culture Techniques; Cerebrovascular Circulation; Disease Models, Animal; Mice; Neuroprotective Agents; Uric Acid; Mus
Type
journal article