Feeding-produced subchronic high plasma levels of uric acid improve behavioral dysfunction in 6-hydroxydopamine-induced mouse model of Parkinson’s disease
Feeding-produced subchronic high plasma levels of uric acid improve behavioral dysfunction in 6-hydroxydopamine-induced mouse model of Parkinson’s disease
复制标题
进食产生的亚慢性高血浆尿酸水平可改善 6-羟基多巴胺诱导的帕金森病小鼠模型的行为功能障碍
DOI：
10.1097/fbp.0000000000000413
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发表时间：
2019
影响因子：
1.6
通讯作者：
Kataoka Yasufumi
中科院分区：
文献类型：
--
作者：
Nakashima Akio;Yamauchi Atsushi;Matsumoto Junichi;Dohgu Shinya;Takata Fuyuko;Koga Mitsuhisa;Fukae Jiro;Tsuboi Yoshio;Kataoka Yasufumi
帕金森病（PD）的发展涉及氧化应激引起的多巴胺能神经元的退化。越来越多的临床证据表明，血液中高浓度的尿酸（UA）（一种内在的抗氧化物质）与降低帕金森病的风险有关。然而，这一假设尚未得到体内实验的证实。本研究调查了 UA 对 PD 发展过程中行为异常的影响。我们使用单侧 6-羟基多巴胺损伤的小鼠，喂食含有 1% UA 和 2.5% 氧酸钾（尿酸酶抑制剂）的饮食来诱导高尿酸血症。在喂食 UA 饮食的组中，发现 UA 水平显着升高。 6-羟基多巴胺损伤的小鼠表现出旋转棒性能受损和阿朴吗啡诱导的对侧旋转增加。通过在手术前 1 周和手术后 5 周饲喂 UA 饮食（亚慢性高尿酸血症），这些行为异常得到显着逆转。这些行为改善与受损纹状体侧酪氨酸羟化酶蛋白水平的恢复同时发生。目前对饮食性高尿酸血症小鼠模型的研究证实，UA 对多巴胺能神经元损失发挥神经保护作用，改善运动功能障碍并改善 PD 的发展。
The development of Parkinson’s disease (PD) involves the degeneration of dopaminergic neurons caused by oxidative stress. Accumulating clinical evidence indicates that high blood levels of uric acid (UA), an intrinsic antioxidative substance, are associated with reduced risk of PD. However, this hypothesis has not been confirmed by in-vivo experiments. The present study investigated the effects of UA on behavioral abnormalities in the development of PD. We used unilateral 6-hydroxydopamine-lesioned mice, which were fed on a diet containing 1% UA and 2.5% potassium oxonate (an uricase inhibitor) to induce hyperuricemia. A significant elevation in UA levels was found in groups that were fed a UA diet. The 6-hydroxydopamine-lesioned mice showed impaired rotarod performance and increased apomorphine-induced contralateral rotations. These behavioral abnormalities were significantly reversed by feeding a UA diet for 1 week before and 5 weeks after surgery (subchronic hyperuricemia). These behavioral improvements occurred in parallel with recovery of tyrosine hydroxylase protein levels in the lesioned striatal side. The present study with a dietary hyperuricemia mice model confirms that UA exerts a neuroprotective effect on dopaminergic neuronal loss, improving motor dysfunction and ameliorating PD development.