Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2 antioxidant signaling pathways
Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2 antioxidant signaling pathways
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DOI：
10.1111/jnc.13087
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发表时间：
2015-06-01
影响因子：
4.7
通讯作者：
Safar, Marwa M.
中科院分区：
文献类型：
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作者：
Abdelsalam, Rania M.;Safar, Marwa M.
格列普汀最近被证明通过调节胰升糖素样肽(GLP)-1来克服细胞培养中的神经元退化。这种在肠道中产生的多肽不仅可以穿过血脑屏障，还可以在大脑中合成，作用于GLP-1R，发挥中枢抗炎和抗细胞凋亡的作用，从而阻止神经元损伤。本研究主要针对RAGE-NFB/NRF2-信号通路，在大鼠鱼藤酮模型上观察二肽基多肽酶(DPP)-4抑制剂维达格列汀的抗帕金森病作用，以判断该药潜在的抗炎/抗氧化作用。维达格列汀显著改善了在开阔场地和旋转棒测试中的运动表现，这种效果随着纹状体多巴胺含量的降低而得到强调。它改变了与体重减轻部分拮抗相关的纹状体能量水平(ADP/ATP)。这种胰岛素增强子抑制了核因子B，从而抑制了下游的炎症介质肿瘤坏死因子。晚期糖化终产物受体(RAGE)的正常化是维达格列汀抗炎作用的主要发现，它与抑制纹状体诱导型一氧化氮合酶、细胞内黏附分子-1和髓过氧化物酶一起发挥抗炎作用。维格列汀的抗氧化潜力被描述为导致硫代巴比妥酸反应物质和转录因子NRF-2水平的减少。维达格列汀通过抑制线粒体基质成分细胞色素c和关键的下游执行因子caspase-3的减少来防止神经元死亡。总之，维达格列汀具有多种神经保护作用，因此有望成为治疗帕金森氏病的候选药物。
Gliptins have been recently shown to conquer neuronal degeneration in cell cultures via modulating glucagon-like peptide (GLP)-1. This peptide produced in the gut not only crosses the blood-brain barrier but is also synthesized in the brain and acts on GLP-1R exerting central anti-inflammatory and antiapoptotic effects, thus impeding neuronal damage. This study investigated the antiparkinsonian effect of vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor in a rat rotenone model targeting mainly the RAGE-NFB/Nrf2-signaling pathways, to judge the potential anti-inflammatory/antioxidant effects of the drug. Vildagliptin markedly improved the motor performance in the open field and rotarod tests, effects that were emphasized by the accompanied reduction in striatal dopamine content. It modified the striatal energy level (ADP/ATP) associated with partial antagonism of body weight reduction. This incretin enhancer suppressed nuclear factor (NF)B and, consequently, the downstream inflammatory mediator tumor necrosis factor-. Normalization of receptor for advanced glycated end product (RAGE) is a main finding which justifies the anti-inflammatory effects of vildagliptin, together with hampering striatal inducible nitric oxide synthase, intracellular adhesion molecule-1 as well as myeloperoxidase. The antioxidant potential of vildagliptin was depicted as entailing reduction in thiobarbituric acid-reactive substances and the transcriptional factor Nrf-2 level. Vildagliptin guarded against neuronal demise through an antiapoptotic effect as reflected by the reduction in the mitochondrial matrix component cytochrome c and the key downstream executioner caspase-3. In conclusion, vildagliptin is endowed with various neuroprotective effects and thus can be a promising candidate for the management of Parkinson's disease.