Omarigliptin Mitigates 6-Hydroxydopamine- or Rotenone-Induced Oxidative Toxicity in PC12 Cells by Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Actions

Abstract

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.

LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis

“…Therefore, the doses of ROT can increase several orders of magnitude, e.g., >330–1600 folds. For instance, the human dopaminergic SH-SH5Y neuroblastoma cells [ 63 ], the Lund human mesencephalic (LUHMES) cell line [ 64 ], iPSC-derived human dopamine neurons [ 65 ], as well as rat adrenal pheochromocytoma PC12 cells [ 66 ], and rat N27 dopaminergic cells [ 67 ] have been exposed to 10–50 μM ROT for different periods of time. In our experimental approach, we exposed the non-dopaminergic HEK-293 LRRK2 WT and KO cells to 50 μM for 6 h, which is a comparable condition to those reported in previously mentioned dopaminergic cell lines.…”

Punicalagin’s Protective Effects on Parkinson’s Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway

“…It is noteworthy that GSK-3β is accompanying to increase the oxidative stress, neuroinflammation, and dopaminergic neuronal apoptosis [73,99,100]. This can be justified by the capability of GSK-3β overexpression to negatively regulate Nrf2/HO-1 activation by promoting Nrf2 degradation while positively regulating NF-KB initiation by facilitating IKBα phosphorylation and NF-KB nuclear translocation [101,102]. Therefore, the observed GSK-3β overexpression might contribute to the ongoing oxidative stress, neuroinflammation, and neuronal apoptosis observed in the SI, MnCl 2 , or SI + MnCl 2 groups.…”

Anti-Inflammatory Effects of Dipeptidyl Peptidase-4 Inhibitors and Their Therapeutic Application for Parkinson's Disease

“…The findings demonstrated that sitagliptin exerted substantial anti-inflammatory effects by modulating the levels of inflammatory factors like Nrf2 and NF-κb (Nader et al 2018). Omarigliptin exhibits anti-inflammatory effects by inhibiting NF-κB activation, leading to a reduction in nitric oxide (NO) production and the expression of inducible NO synthase (iNOS) in a model of neurotoxin-induced toxicity in PC12 cells, which mimics PD (Gouda and Cho 2022).…”