Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino 142290, Russia.
Pushchino State Natural Science Institute, Pushchino 142290, Russia.
Int J Mol Sci. 2023 Sep 19;24(18):14304. doi: 10.3390/ijms241814304.
Using a model of Parkinson's disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity. Structural changes occurring in the SN and striatum manifested themselves in the destruction of mitochondria, degeneration of neurons and synapses, and stratification of myelin sheaths in them. Subcutaneous injections of 30 µg/kg uridine for 22 days restored the neurotoxin-induced changes in these parameters to levels close to the control. 5-Hydroxydecanoate (5 mg/kg), a specific mitoK-ATP channel inhibitor, eliminated the beneficial effect of uridine for almost all characteristics tested, indicating the involvement of the mitoK-ATP channel in the protective effect of uridine. The mechanism of the protective effect of uridine and its therapeutic applications for the prevention and treatment of PD are discussed.
使用双侧注射神经毒素 6-羟多巴胺（6-OHDA）到大鼠脑黑质（SN）诱导帕金森病（PD）模型，我们发现尿苷发挥保护作用与线粒体 ATP 依赖性钾通道（mitoK-ATP 通道）的激活有关。注射 4µg 神经毒素后，在转棒测试中，实验动物在棒上的时间减少了 70%，血清和大脑皮质线粒体中的脂质过氧化物含量增加，活性氧形成率增加，线粒体中 Ca 的保留减少。与此同时，淋巴细胞中糖酵解细胞质酶乳酸脱氢酶的活性增加，而琥珀酸脱氢酶的活性没有变化。SN 和纹状体中发生的结构变化表现为线粒体破坏、神经元和突触退化以及髓鞘分层。皮下注射 30µg/kg 尿苷 22 天可使这些参数的神经毒素诱导变化恢复到接近对照的水平。5-羟基癸酸（5mg/kg），一种特异性 mitoK-ATP 通道抑制剂，几乎消除了尿苷的所有测试特征的有益作用，表明 mitoK-ATP 通道参与了尿苷的保护作用。讨论了尿苷的保护作用机制及其在预防和治疗 PD 中的治疗应用。
