Gouda Noha A, Cho Jungsook
College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang 10326, Gyeonggi, Korea.
Antioxidants (Basel). 2022 Sep 28;11(10):1940. doi: 10.3390/antiox11101940.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are reported to exhibit promising effects on several pathological processes associated with Parkinson's disease (PD). To explore its repositioning potential as an antiparkinsonian agent, we evaluated the effects of omarigliptin (OMG), a DPP-4 inhibitor recently approved as a hypoglycemic drug, on neurotoxin-induced toxicity, using PC12 cells as a cellular model of PD. The molecular mechanism(s) underlying its protective activity was also investigated. OMG alleviated oxidative toxicity and the production of reactive oxygen species induced by 6-hydroxydopamine (6-OHDA) or rotenone. It also partially attenuated the formation of DPPH radicals and lipid peroxidation, demonstrating the antioxidant properties of OMG. OMG upregulated Nrf2 and heme oxygenase-1 (HO-1). Notably, treatment with a selective HO-1 inhibitor and Nrf2 knockdown by siRNA abolished the beneficial effects of OMG, indicating that the activated Nrf2/HO-1 signaling was responsible for the protective activity. Moreover, OMG exhibited anti-inflammatory activity, blocking inflammatory molecules, such as nitric oxide (NO) and inducible NO synthase, through inhibition of IκBα phosphorylation and NF-κB activation in an Akt-dependent fashion. Finally, OMG decreased the levels of cleaved caspase-3 and Bax and increased the level of Bcl-2, indicating its anti-apoptotic properties. Collectively, these results demonstrate that OMG alleviates the neurotoxin-induced oxidative toxicity through Nrf2/HO-1-mediated antioxidant, NF-κB-mediated anti-inflammatory, and anti-apoptotic mechanisms in PC12 cells. Our findings elucidating multiple mechanisms of antiparkinsonian activity strongly support the therapeutic potential of OMG in the treatment of PD.
据报道，二肽基肽酶4（DPP-4）抑制剂对帕金森病（PD）相关的几种病理过程具有显著作用。为了探索其作为抗帕金森病药物的重新定位潜力，我们使用PC12细胞作为PD的细胞模型，评估了最近被批准作为降糖药物的DPP-4抑制剂奥格列汀（OMG）对神经毒素诱导的毒性的影响。还研究了其保护活性的分子机制。OMG减轻了6-羟基多巴胺（6-OHDA）或鱼藤酮诱导的氧化毒性和活性氧的产生。它还部分减弱了DPPH自由基的形成和脂质过氧化，证明了OMG的抗氧化特性。OMG上调了Nrf2和血红素加氧酶-1（HO-1）。值得注意的是，用选择性HO-1抑制剂处理和通过siRNA敲低Nrf2消除了OMG的有益作用，表明激活的Nrf2/HO-1信号通路是保护活性的原因。此外，OMG表现出抗炎活性，通过以Akt依赖的方式抑制IκBα磷酸化和NF-κB激活来阻断炎症分子，如一氧化氮（NO）和诱导型NO合酶。最后，OMG降低了裂解的caspase-3和Bax的水平，并增加了Bcl-2的水平，表明其抗凋亡特性。总的来说，这些结果表明，OMG通过PC12细胞中Nrf2/HO-1介导的抗氧化、NF-κB介导的抗炎和抗凋亡机制减轻了神经毒素诱导的氧化毒性。我们对帕金森病活性多种机制的研究结果有力地支持了OMG在治疗PD方面的治疗潜力。
