Department of Pharmacology, School of Medicine, University of Navarra, Pamplona, Spain.
Neurobiol Dis. 2010 May;38(2):237-45. doi: 10.1016/j.nbd.2010.01.013. Epub 2010 Jan 25.
In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD.
在这项研究中，我们测试了磷酸二酯酶 5 (PDE5) 抑制剂西地那非和伐地那非是否能预防 3-硝基丙酸 (3NP) 引起的损伤，3NP 可引起纹状体损伤，与亨廷顿病 (HD) 的一些神经病理学特征非常相似。神经毒素通过恒速系统输注渗透微型泵在 5 天内给药。用 PDE5 抑制剂（西地那非或伐地那非）治疗的动物表现出改善的神经评分，减少纹状体 DARPP-32 蛋白水平和损伤体积的丧失，并减少 3NP 引起的钙蛋白酶激活。这种保护作用与 3NP 诱导的琥珀酸脱氢酶抑制的变化无关。此外，西地那非治疗的大鼠纹状体 p-CREB 水平以及 BDNF 的表达显著增加。总之，PDE5 抑制剂通过减少钙蛋白酶激活和促进存活途径来预防 3NP 诱导的纹状体变性。这些数据鼓励进一步评估 PDE5 抑制剂在 HD 的转基因小鼠模型中的应用。
