Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice.
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.
Haberman
Frank
F
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD, USA.
Tang
Sung-Chun
SC
Arumugam
Thiruma V
TV
Hyun
Dong-Hoon
DH
Yu
Qian-Sheng
QS
Cutler
Roy G
RG
Guo
Zhihong
Z
Holloway
Harold W
HW
Greig
Nigel H
NH
Mattson
Mark P
MP
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy*; D002545:Brain Ischemia / Q000188:drug therapy*; D018929:Cell Culture Techniques; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D000975:Antioxidants; D018696:Neuroprotective Agents; D014527:Uric Acid; C039222:1,3,7-trimethyluric acid; C053084:1,7-dimethyluric acid