Beneficial effects of linagliptin in cell culture model of Parkinson’s disease

Year 2022, Volume: 8 Issue: 2, 242 - 246, 04.03.2022

Ufuk Okkay , Irmak Ferah Okkay

https://doi.org/10.18621/eurj.1010322

Cited By: 4

Abstract

Objectives: We aimed to investigate the neuroprotective effects of linagliptin in an in vitro 6-hydroxydopamine (6-OHDA) Parkinson’s disease model.

Methods: 6-OHDA (200 µM) were administered to the SH-SY5Y cells for 24 h to induce Parkinson’s disease model in vitro. Cells were treated with linagliptin (1, 10, 50 and 100 nM) 30 minutes before 6-OHDA administration. Cell viability was examined by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method and lactate dehydrogenase (LDH) analysis. Superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and reactive oxygen species (ROS) analyses were conducted to assess oxidative stress. Apoptosis was evaluated with Caspase-3 mRNA expression levels.

Results: It was observed that 6-OHDA elevated LDH levels and cell death. Oxidative stress was exaggerated with increased ROS and MDA levels and substantially apoptosis was proven with increased Caspase-3 levels in SH-SY5Y cells. Pretreatment with linagliptin alleviated oxidative stress and apoptosis.

Conclusions: Given its neuroprotective role as well as its effects on oxidative stress and apoptosis, linagliptin may be a drug candidate in Parkinson's disease.

Keywords

6-OHDA, DPP-4 inhibitor, linagliptin, Parkinson’s disease, SH-SY5Y cells

References

• 1. Chahine LM, Amara AW, Videnovic A. A systematic review of the literature on disorders of sleep and wakefulness in Parkinson's disease from 2005 to 2015. Sleep Med Rev 2017;35:33-50.
• 2. Olanow CW, Stern MB. Parkinson's disease: unresolved issues. Ann Neurol 2008;64 Suppl 2:S1-2.
• 3. Hirsch EC, Hunot S, Faucheux B, Agid Y, Mizuno Y, Mochizuki H, et al. Dopaminergic neurons degenerate by apoptosis in Parkinson's disease. Mov Disord 1999;14:383-5.
• 4. Miller RL, James-Kracke M, Sun GY, Sun AY. Oxidative and inflammatory pathways in Parkinson's disease. Neurochem Res 2009;34:55-65.
• 5. Reeve A, Simcox E, Turnbull D. Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Ageing Res Rev 2014;14:19-30.
• 6. Foltynie T, Kahan J. Parkinson's disease: an update on pathogenesis and treatment. J Neurol 2013;260:1433-40.
• 7. Ossig C, Reichmann H. Treatment of Parkinson's disease in the advanced stage. J Neural Transm (Vienna) 2013;120:523-9.
• 8. Kosaraju J, Holsinger RMD, Guo L, Tam KY. Linagliptin, a Dipeptidyl peptidase-4 inhibitor, mitigates cognitive deficits and pathology in the 3xTg-AD mouse model of Alzheimer's disease. Mol Neurobiol 2017;54:6074-84.
• 9. Darsalia V, Ortsater H, Olverling A, Darlof E, Wolbert P, Nystrom T, et al. The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride. Diabetes 2013;62:1289-96.
• 10. McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 2011;31:6587-94.
• 11. Duffy AM, Holscher C. The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer's disease. Neuroscience 2013;228:294-300.
• 12. Xicoy H, Wieringa B, Martens GJ. The SH-SY5Y cell line in Parkinson's disease research: a systematic review. Mol Neurodegener 2017;12:10.
• 13. Hernandez-Baltazar D, Zavala-Flores LM, Villanueva-Olivo A. The 6-hydroxydopamine model and parkinsonian pathophysiology: novel findings in an older model. Neurologia 2017;32:533-9.
• 14. Li H, Zhang J, Lin L, Xu L. Vascular protection of DPP-4 inhibitors in retinal endothelial cells in in vitro culture. Int Immunopharmacol 2019;66:162-8.
• 15. Shi S, Kanasaki K, Koya D. Linagliptin but not sitagliptin inhibited transforming growth factor-beta2-induced endothelial DPP-4 activity and the endothelial-mesenchymal transition. Biochem Biophys Res Commun 2016;471:184-90.
• 16. Nakamura Y, Inagaki M, Tsuji M, Gocho T, Handa K, Hasegawa H, et al. Linagliptin has wide-ranging anti-inflammatory points of action in human umbilical vein endothelial cells. Jpn Clin Med 2016;7:27-32.
• 17. Okkay U, Ferah Okkay I, Aydin IC, Bayram C, Ertugrul MS, Gezer A, et al. Effects of Achillea millefolium on cisplatin induced ocular toxicity: an experimental study. Cutan Ocul Toxicol 2021;40:214-20.
• 18. Okkay U, Ferah Okkay I, Cicek B, Aydin IC, Ertugrul MS, Bayram C, et al. Achillea millefolium alleviates testicular damage in paclitaxel-intoxicated rats via attenuation of testicular oxido-inflammatory stress and apoptotic responses. Andrologia 2021;53:e14028.
• 19. Calsolaro V, Edison P. Novel GLP-1 (Glucagon-Like Peptide-1) analogues and insulin in the treatment for Alzheimer's disease and other neurodegenerative diseases. CNS Drugs 2015;29:1023-39.
• 20. Holscher C. Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer's disease. Recent Pat CNS Drug Discov 2010;5:109-17.
• 21. Shannon RP. DPP-4 inhibition and neuroprotection: do mechanisms matter? Diabetes 2013;62:1029-31.
• 22. Ji C, Xue GF, Lijun C, Feng P, Li D, Li L, et al. A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson's disease by increasing expression of BNDF. Brain Res 2016;1634:1-11.
• 23. Spencer B, Potkar R, Metcalf J, Thrin I, Adame A, Rockenstein E, et al. Systemic central nervous system (CNS)-targeted delivery of neuropeptide Y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of Alzheimer disease. J Biol Chem 2016;291:1905-20.
• 24. Xu Z, Yang D, Huang X, Huang H. Astragaloside IV protects 6-hydroxydopamine-induced SH-SY5Y cell model of Parkinson's disease via activating the JAK2/STAT3 pathway. Front Neurosci 2021;15:631501.
• 25. Medeiros MS, Schumacher-Schuh A, Cardoso AM, Bochi GV, Baldissarelli J, Kegler A, et al. Iron and oxidative stress in Parkinson's disease: an observational study of injury biomarkers. PLoS One 2016;11:e0146129.
• 26. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005;55:178-94.
• 27. El-Deeb OS, Soliman GM, Elesawy RO. Linagliptin, the dipeptidyl peptidase-4 enzyme inhibitor, lessens CHOP and GRP78 biomarkers levels in cisplatin-induced neurobehavioral deficits: A possible restorative gateway. J Biochem Mol Toxicol 2020:e22541.