Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice
Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice
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DOI：
10.1007/s12017-007-8010-1
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
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作者：
Haberman, Frank;Tang, Sung-Chun;Mattson, Mark P.
尿酸是人类血液中的主要抗氧化剂，可以保护培养的神经元免受氧化和代谢损伤。然而，尿酸具有非常低的溶解度，这损害了它在神经退行性疾病的潜在临床应用。在这里，我们描述的合成，表征和临床前开发的神经保护甲基和含硫类似物尿酸增加溶解度。体外和细胞培养筛选鉴定1,7-二甲基尿酸（mUA2）和6,8-二硫尿酸（sUA2）是两种具有高抗氧化和神经保护活性的类似物。在小鼠脑缺血再灌注模型中，静脉注射尿酸类似物mUA2和sUA2可减轻脑损伤并改善功能结果。类似物sUA2和mUA2在永久性大脑中动脉闭塞小鼠模型中风发作后4小时给予时，也能有效减少对大脑皮层的损伤。这些发现表明可溶性尿酸类似物在治疗中风和相关神经退行性疾病方面具有治疗潜力。
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.