Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model
Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model
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DOI：
10.1007/s12035-018-0923-1
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发表时间：
2018-09-01
影响因子：
5.1
通讯作者：
Bahgat, Ashraf K.
中科院分区：
文献类型：
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作者：
Hedya, Shireen A.;Safar, Marwa M.;Bahgat, Ashraf K.
核受体相关1（Nurr 1）孤儿受体已成为改善帕金森病的一个有前途的竞争者，因此，寻找合适的Nurr 1受体激活剂是治疗PD的一个有吸引力的目标。西洛他唑是一种磷酸二酯酶-3抑制剂，最近在多种破坏性中枢疾病中显示出良好的神经保护活性，但该药物可能的抗帕金森病活性尚未完全阐明。因此，本研究旨在探讨西洛他唑对鱼藤酮诱导的PD大鼠模型的神经保护作用。西洛他唑成功地上调了PD大鼠的Nurr 1表达，这导致多巴胺能神经元功能和完整性的成功保存，如通过旋转棒和旷场测试中运动性能的显著改善以及纹状体酪氨酸羟化酶含量的增加所证实的。此外，西洛他唑显示出抗炎活性，如通过Nurr-1上调和糖原合成酶激酶3 β GSK-3 β抑制，阻碍炎症信号传导途径的全局控制器核因子-κ B及其下游促炎细胞因子，即肿瘤坏死因子-α和白细胞介素-1 β。反过来，GSK-3 β抑制形式的增加抑制了测量的下游凋亡生物标志物，即细胞色素C和半胱天冬酶-3。值得注意的是，西洛他唑增强了自噬，如通过阻碍LC 3-II和P62水平所描述的，可能是通过沉默调节蛋白1水平的显著升高。总之，西洛他唑通过调节Nurr 1表达以及SIRT-1/自噬和GSK-3 β/凋亡交叉调节，可能成为PD治疗的有希望的候选药物。
Nuclear receptor related 1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson's disease: thus, finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Cilostazol, a phosphodiesterase-3 inhibitor, recently showed a favorable neuroprotective activity in multiple devastating central disorders, yet the possible antiparkinsonian activity of the drug has not been fully elucidated. Thus, the aim of this study is to explore the neuroprotective effect of cilostazol in rotenone-induced PD model in rats. Cilostazol successfully upregulated Nurr1 expression in PD rats, which resulted in successful preservation of the dopaminergic neuron functionality and integrity as verified by the marked improvement of motor performance in rotarod and open field tests, as well as the increased striatel tyrosine hydroxylase content. Moreover, cilostazol revealed an anti-inflammatory activity as manifested by hampering the global controller of inflammatory signaling pathway, nuclear factor-kappa B, together with its downstream pro-inflammatory cytokines, namely tumor necrosis factor-alpha and interleukin-1 beta, via Nurr-1 upregulation and glycogen synthase kinase 3 beta GSK-3 beta inhibition. In turn, the increase in GSK-3 beta inhibited form suppressed the measured downstream apoptotic biomarkers, viz. cytochrome C and caspase-3. Remarkably, cilostazol enhanced autophagy as depicted by hampering both LC3-II and P62 levels possibly through the prominent rise in sirtuin 1 level. In conclusion, cilostazol could be a promising candidate for PD treatment through modulating Nurr1 expression, as well as SIRT-1/autophagy, and GSK-3 beta/apoptosis cross-regulation.