Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease.
Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease.
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DOI：
10.1016/j.ebiom.2018.10.039
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发表时间：
2018-11
期刊：
影响因子：
11.1
通讯作者：
Parkinson Study Group (PSG) The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) investigators
中科院分区：
文献类型：
--
作者：
Chen X;Umeh CC;Tainsh RE;Feng DD;Maguire M;Zuo F;Rahimian M;Logan R;Wang X;Ascherio A;Macklin EA;Buys ES;Schwarzschild MA;Parkinson Study Group (PSG) The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) investigators
流行病学、实验室和临床研究已经确定尿酸盐升高与高血压（BP）之间存在关联。然而，因果关系的推断仍然存在争议。天然存在的抗氧化剂，尿酸盐也可能是神经保护性的，并且用其前体肌苷升高尿酸盐治疗目前正在临床开发中，作为帕金森病（PD）的潜在疾病修饰策略。我们的研究利用了最近完成的一项II期试验，评估了口服肌苷在无重大心血管和肾脏疾病的从头非致残早期PD中的作用，并利用了三种基因工程小鼠：尿酸氧化酶（UOx）全基因敲除（gKO）、条件性KO（cKO）和转基因（Tg）小鼠分别具有显著升高、轻度升高和显著降低的血清尿酸盐，系统研究调尿酸手法对血压的影响。在临床试验参与者中，不同治疗组的血清尿酸盐变化不同，而收缩压、舒张压和直立位血压变化无差异。尿酸盐升高与收缩压、舒张压和直立位血压变化之间无正相关性（p = 0.05（反向），分别为0.30和0.63）。在UOx gKO、cKO或Tg小鼠与其各自的野生型同窝小鼠之间，收缩压或舒张压或其对BP调节干预的反应无显著差异。我们在动物模型和一般健康的早期PD中进行的补充性临床前和人体尿酸盐调节研究不支持尿酸盐升高的高血压效应或尿酸盐与BP之间的相关性。美国国防部、RJG基金会、迈克尔·J·福克斯基金会LEAPS计划、美国国立卫生研究院、美国老龄研究联合会、帕金森病基金会推进帕金森病治疗倡议。
Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative.
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影响因子：
4.1
作者：
Huang, Xinxin;Ng, Samuel Yong-Ern;Tan, Louis Chew-Seng
通讯作者：
Tan, Louis Chew-Seng
DOI：
10.1073/pnas.78.11.6858
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
AMES, BN;CATHCART, R;HOCHSTEIN, P
通讯作者：
HOCHSTEIN, P
尿酸盐的神经保护作用是通过增强星形胶质细胞谷胱甘肽的合成和释放来介导的
影响因子：
6.1
作者：
Bakshi R;Zhang H;Logan R;Joshi I;Xu Y;Chen X;Schwarzschild MA
通讯作者：
Schwarzschild MA
DOI：
10.1124/jpet.107.129031
发表时间：
2008-01-01
影响因子：
3.5
作者：
Kutzing, Melinda K.;Firestein, Bonnie L.
通讯作者：
Firestein, Bonnie L.
影响因子：
4.7
作者：
Johnson, Richard J.;Gaucher, Eric A.;Benner, Steven A.
通讯作者：
Benner, Steven A.