Attenuation of acrylamide-induced neurotoxicity by supplementation of sitagliptin in Wistar rats

Document Type : Original Article


1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Acrylamide (ACR) induces neurotoxicity in humans and animals through different mechanisms. Sitagliptin is a type-2 diabetes medication with neuroprotective properties. The effects of sitagliptin against neurotoxicity stimulated by ACR were examined.
Materials and Methods: Male Wistar rats were classified as follows: 1. Control (normal saline, 11 days, IP), 2. ACR (50 mg/kg, 11 days, IP), 3. ACR (11 days, days 11-20 normal saline), 4-7. ACR+sitagliptin (5, 10, 20, and 40 mg/kg, 11 days, IP), 8. ACR+sitagliptin (10 mg/kg, days 6-11), 9. ACR+sitagliptin (10 mg/kg, days 6-20), 10. Sitagliptin (40 mg/kg, 11 days), 11. ACR+vitamin E (200 mg/kg, IP). Finally, the gait score was evaluated. Reduced glutathione (GSH) and malondialdehyde (MDA) levels were measured in cortex tissue.  Also, IL-1β, TNF-α, and caspase-3 levels were assessed in the cortex by western blotting. 
Results: ACR caused movement disorders, triggered oxidative stress, and raised TNF-α, IL-1β, and caspase-3 cleaved levels. Supplementation of sitagliptin (10 mg/kg) along with ACR, in 3 protocols, reduced gait disorders compared to the ACR group. Receiving sitagliptin in all doses plus ACR and injection of sitagliptin (10 mg/kg) from days 6 to11 reduced the MDA level of cortex tissue. Sitagliptin (all doses) plus ACR increased the GSH level of the cortex tissue. Sitagliptin (10 mg/kg) with ACR dropped the amounts of TNF-α and caspase-3 cleaved proteins in cortex tissue but did not affect the IL-1β level.
Conclusion: Sitagliptin disclosed preventive and therapeutic effects on ACR neurotoxicity. Sitagliptin possesses antioxidant, anti-inflammatory, and anti-apoptotic properties and inhibits CR neurotoxicity in rats. 


Main Subjects

1. Koszucka A, Nowak A, Nowak I, Motyl I. Acrylamide in human diet, its metabolism, toxicity, inactivation and the associated European Union legal regulations in food industry. Crit Rev Food Sci Nutr 2020; 60:1677-1692.
2. Ghasemzadeh Rahbardar M, Hemadeh B, Razavi BM, Eisvand F, Hosseinzadeh H. Effect of carnosic acid on acrylamide induced neurotoxicity: in vivo and in vitro experiments. Drug Chem Toxicol 2020; 45:1528-1535.
3. Kianfar M, Nezami A, Mehri S, Hosseinzadeh H, Hayes AW, Karimi G. The protective effect of fasudil against acrylamide-induced cytotoxicity in PC12 cells. Drug Chem Toxicol 2020; 43:595-601.
4. Wei X, Yan F, Meng E, Zhang C, Li G, Yang X, et al. Neuroprotective effect of calpeptin on acrylamide-induced neuropathy in rats. Neurochem Res 2015; 40:2325-2332.
5. Yazadanpanah Z, Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Investigating the effect of telmisartan on acrylamide-induced neurotoxicity through in vitro and in vivo methods. Iran J Basic Med Sci 2023; 26:1024-1029.
6. Foroutanfar A, Mehri S, Kamyar M, Tandisehpanah Z, Hosseinzadeh H. Protective effect of punicalagin, the main polyphenol compound of pomegranate, against acrylamide‐induced neurotoxicity and hepatotoxicity in rats. Phytother Res 2020; 34:3262-3272.
7. Karimi M, Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Amifostine inhibits acrylamide-induced hepatotoxicity by inhibiting oxidative stress and apoptosis. Iran J Basic Med Sci 2023; 26:662-668.
8. Hung C-C, Cheng Y-W, Chen W-L, Fang W-H. Negative association between acrylamide exposure and metabolic syndrome markers in adult population. Int J Environ Res Public Health 2021; 18:11949.
9. Rameshrad M, Razavi BM, Ferns GA, Hosseinzadeh H. Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning. DARU 2019; 27:341-360.
10. Rameshrad M, Razavi BM, Lalau J-D, De Broe ME, Hosseinzadeh H. An overview of glucagon-like peptide-1 receptor agonists for the treatment of metabolic syndrome: A drug repositioning. Iran J Basic Med Sci 2020; 23:556-558.
11. Pennisi M, Malaguarnera G, Puglisi V, Vinciguerra L, Vacante M, Malaguarnera M. Neurotoxicity of acrylamide in exposed workers. Int J Environ Res Public Health 2013; 10:3843-3854.
12. Sengul E, Gelen V, Yildirim S, Tekin S, Dag Y. The Effects of Selenium in Acrylamide-Induced Nephrotoxicity in Rats: Roles of Oxidative Stress, Inflammation, Apoptosis, and DNA Damage. Biol Trace Elem Res 2021; 199:173-184.
13. Goudarzi M, Mombeini MA, Fatemi I, Aminzadeh A, Kalantari H, Nesari A, et al. Neuroprotective effects of Ellagic acid against acrylamide-induced neurotoxicity in rats. Neurol Res 2019; 41:419-428.
14. Kurebayashi H, Ohno Y. Metabolism of acrylamide to glycidamide and their cytotoxicity in isolated rat hepatocytes: protective effects of GSH precursors. Arch Toxicol 2006; 80:820-828.
15. Scott LJ. Sitagliptin: a review in type 2 diabetes. Drugs 2017; 77:209-224.
16. Wiciński M, Wódkiewicz E, Słupski M, Walczak M, Socha M, Malinowski B, et al. Neuroprotective activity of sitagliptin via reduction of neuroinflammation beyond the incretin effect: Focus on Alzheimer’s disease. Biomed Res Int 2018; 2018:6091014.
17. Li Y, Zheng M, Sah SK, Mishra A, Singh Y. Neuroprotective influence of sitagliptin against cisplatin-induced neurotoxicity, biochemical and behavioral alterations in Wistar rats. Mol Cell Biochem 2019; 455:91-97.
18. Jo CH, Kim S, Park J-S, Kim G-H. Anti-inflammatory action of sitagliptin and linagliptin in doxorubicin nephropathy. Kidney Blood Press Res 2018; 43:987-999.
19. El-Sahar AE, Safar MM, Zaki HF, Attia AS, Ain-Shoka AA. Sitagliptin attenuates transient cerebral ischemia/reperfusion injury in diabetic rats: Implication of the oxidative–inflammatory–apoptotic pathway. Life Sci 2015; 126:81-86.
20. Abuelezz SA, Hendawy N, Abdel Gawad S. Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity. J Pharm Pharmacol 2016; 68:523-532.
21. Ghasemzadeh Rahbardar M, Cheraghi Farmed H, Hosseinzadeh H, Mehri S. Protective effects of selenium on acrylamide-induced neurotoxicity and hepatotoxicity in rats. Iran J Basic Med Sci 2021; 24:1041-1049.
22. Mehri S, Abnous K, Khooei A, Mousavi SH, Shariaty VM, Hosseinzadeh H. Crocin reduced acrylamide-induced neurotoxicity in Wistar rat through inhibition of oxidative stress. Iran J Basic Med Sci 2015; 18:902-908.
23. Mondragon A, Davidsson D, Kyriakoudi S, Bertling A, Gomes-Faria R, Cohen P, et al. Divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia. PLoS One 2014; 9:e104873.
24. Mehri S, Shahi M, Razavi BM, Hassani FV, Hosseinzadeh H. Neuroprotective effect of thymoquinone in acrylamide-induced neurotoxicity in Wistar rats. Iran J Basic Med Sci 2014; 17:1007-1011.
25. Tabeshpour J, Mehri S, Abnous K, Hosseinzadeh H. Neuroprotective effects of thymoquinone in acrylamide-induced peripheral nervous system toxicity through MAPKinase and apoptosis pathways in rat. Neurochem Res 2019; 44:1101-1112.
26. Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta Gen Subj 1979; 582:67-78.
27. Rahbardar MG, Eisvand F, Rameshrad M, Razavi BM, Hosseinzadeh H. In vivo and in vitro protective effects of rosmarinic acid against doxorubicin-induced cardiotoxicity. Nutr Cancer 2021; 74:747-760.
28. Shahroudi MJ, Mehri S, Hosseinzadeh H. Anti-aging effect of Nigella sativa fixed oil on D-galactose-induced aging in mice. J Pharmacopuncture 2017; 20:29-35.
29. Ghobakhlou F, Eisvand F, Razavi BM, Ghasemzadeh Rahbardar M, Hosseinzadeh H. Evaluating the effect of alpha-mangostin on neural toxicity induced by acrylamide in rats. Environ Sci Pollut Res Int. 2023; 30:95789-95800. 
30. Uchiyama M, Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86:271-278.
31. Oskouei Z, Mehri S, Kalalinia F, Hosseinzadeh H. Evaluation of the effect of thymoquinone in d‐galactose‐induced memory impairments in rats: Role of MAPK, oxidative stress, and neuroinflammation pathways and telomere length. Phytother Res 2021; 35:2252-2266.
32. Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Investigating the ameliorative effect of alpha‐mangostin on development and existing pain in a rat model of neuropathic pain. Phytother Res 2020; 34:3211-3225.
33. Ghasemzadeh Rahbardar M, Razavi BM, Naraki K, Hosseinzadeh H. Therapeutic effects of minocycline on oleic acid-induced acute respiratory distress syndrome (ARDS) in rats. Naunyn Schmiedebergs Arch Pharmacol 2023:1-10.
34. LoPachin RM, Gavin T. Molecular mechanism of acrylamide neurotoxicity: lessons learned from organic chemistry. Environ Health Perspect 2012; 120:1650-1657.
35. Mehri S, Karami HV, Hassani FV, Hosseinzadeh H. Chrysin reduced acrylamide-induced neurotoxicity in both in vitro and in vivo assessments. Iran Biomed J 2014; 18:101-106.
36. Mehri S, Dadesh Q, Tabeshpour J, Vahdati Hassani F, Karimi G, Hosseinzadeh H. Evaluation of the neuroprotective effect of silymarin on acrylamide-induced neurotoxicity. Jundishapur J Nat Pharm Prod 2016; 11:e37644.
37. Mehri S, Meshki MA, Hosseinzadeh H. Linalool as a neuroprotective agent against acrylamide-induced neurotoxicity in Wistar rats. Drug Chem Toxicol 2015; 38:162-166.
38. Wang CH, Zhu N. Protective role of sitagliptin against oxidative stress in a kainic acid‐induced status epilepticus in rats models via Nrf2/HO‐1 pathway. Drug Dev Res 2019; 80:446-452.
39. Liu Y, Zhang X, Yan D, Wang Y, Wang N, Liu Y, et al. Chronic acrylamide exposure induced glia cell activation, NLRP3 infl-ammasome upregulation and cognitive impairment. Toxicol Appl Pharmacol 2020; 393:114949.
40. Acaroz U, Ince S, Arslan-Acaroz D, Gurler Z, Kucukkurt I, Demirel HH, et al. The ameliorative effects of boron against acrylamide-induced oxidative stress, inflammatory response, and metabolic changes in rats. Food Chem Toxicol 2018; 118:745-752.
41. Guo J, Cao X, Hu X, Li S, Wang J. The anti-apoptotic, anti-oxidant and anti-inflammatory effects of curcumin on acrylamide-induced neurotoxicity in rats. BMC Pharmacol Toxicol 2020; 21:62.
42. Tsai T-H, Sun C-K, Su C-H, Sung P-H, Chua S, Zhen Y-Y, et al. Sitagliptin attenuated brain damage and cognitive impairment in mice with chronic cerebral hypo-perfusion through suppressing oxidative stress and inflammatory reaction. J Hypertens 2015; 33:1001-1013.
43. Kim B, Yun J, Park B. Methamphetamine-induced neuronal damage: neurotoxicity and neuroinflammation. Biomol Ther 2020; 28:381-388.
44. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Mol Cell 2010; 37:299-310.
45. Gavathiotis E, Reyna DE, Davis ML, Bird GH, Walensky LD. BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell 2010; 40:481-492.
46. Kekre N, Griffin C, McNulty J, Pandey S. Pancratistatin causes early activation of caspase-3 and the flipping of phosphatidyl serine followed by rapid apoptosis specifically in human lymphoma cells. Cancer Chemother Pharmacol 2005; 56:29-38.
47. Salvesen GS, Dixit VM. Caspase activation: the induced-proximity model. Proc Natl Acad Sci U S A 1999; 96:10964-10967.
48. He Y, Tan D, Bai B, Wu Z, Ji S. Epigallocatechin-3-gallate attenuates acrylamide-induced apoptosis and astrogliosis in rat cerebral cortex. Toxicol Mech Methods 2017; 27:298-306.