Carvedilol attenuates acrylamide-induced brain damage through inhibition of oxidative, inflammatory, and apoptotic mediators

Document Type : Original Article


1 Department of Pharmacology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

2 Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran


Objective(s): Acrylamide is a potent neurotoxic compound and has harmful effects on brain cells. Acrylamide promotes oxidative, inflammatory, and apoptotic mediators in the CNS leading to neurological disorders. The goal of the current study was to examine the potential protective effect of carvedilol and its underlying mechanisms in a mouse model of acrylamide-induced brain injury. 
Materials and Methods: Mice were treated with acrylamide (50 mg/kg/day, IP) and carvedilol (5 and 10 mg/kg/day, oral) for 11 continuous days. At the end of the experiment, mice were subjected to gait assessment. They were sacrificed and brain tissues were collected for histological and biochemical analysis. 
Results: The results showed that treatment of mice with carvedilol decreased acrylamide-induced bodyweight loss, abnormal gait, and histopathological damage in the brain tissue. Carvedilol treatment significantly reduced the levels of malondialdehyde (MDA) and carbonyl protein and increased the levels of glutathione (GSH), catalase, superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Carvedilol treatment also decreased myeloperoxidase (MPO) activity, expression of nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), overproduction of nitric oxide (NO) and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the brain of mice exposed to acrylamide. Furthermore, administration of carvedilol significantly decreased the levels of bax, cytochrome-c, and caspase-3 as markers of apoptosis in acrylamide-treated mice. 
Conclusion: These findings indicate that carvedilol is able to attenuate acrylamide-induced damage to the CNS by inhibition of oxidative stress, inflammation, and apoptosis. 


1. Amirshahrokhi K. Acrylamide exposure aggravates the development of ulcerative colitis in mice by the activation of proinflammatory cytokines, NF-κB, iNOS and oxidative stress. Iran J Basic Med Sci 2021; 24:312-321.
2. 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.
3. Matoso V, Bargi-Souza P, Ivanski F, Romano MA, Romano RM. Acrylamide: A review about its toxic effects in the light of Developmental Origin of Health and Disease (DOHaD) concept. Food Chem 2019; 15;283:422-430.
4. Elhelaly AE, AlBasher G, Alfarraj S, Almeer R, Bahbah EI, Fouda MMA, et al. Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats. Environ Sci Pollut Res Int 2019; 26:35151-35162. 
5. Sui X, Yang J, Zhang G, Yuan X, Li W, Long J, et al. NLRP3 inflammasome inhibition attenuates subacute neurotoxicity induced by acrylamide in vitro and in vivo. Toxicology 2020; 28:432:152392.
6. Elblehi SS, El Euony OI, El-Sayed YS. Apoptosis and astrogliosis perturbations and expression of regulatory inflammatory factors and neurotransmitters in acrylamide-induced neurotoxicity under ω3 fatty acids protection in rats. Neurotoxicology 2020; 76:44-57.
7. Tabeshpour J, Mehri S, Abnous K, Hosseinzadeh H. Role of oxidative stress, MAPKinase and apoptosis pathways in the protective effects of thymoquinone against acrylamide-induced central nervous system toxicity in rat. Neurochem Res 2020; 45:254–267.
8. Thabet NM, Moustafa EM. Protective effect of rutin against brain injury induced by acrylamide or gamma radiation: role of PI3K/AKT/GSK-3b/NRF-2 signalling pathway. Arch Physiol Biochem 2018; 124:185-193. 
9. Zhao M, Lewis Wang FS, Hu X, Chen F, Chan HM. Acrylamide-induced neurotoxicity in primary astrocytes and microglia: Roles of the Nrf2-ARE and NF-κB pathways. Food Chem Toxicol 2017; 106(Pt A):25-35.
10. Hamdy N, El-Demerdash E. New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. Toxicol Appl Pharmacol 2012; 15;261:292-299. 
11. Amirshahrokhi K, Khalili AR. Carvedilol attenuates paraquat-induced lung injury by inhibition of proinflammatory cytokines, chemokine MCP-1, NF-κB activation and oxidative stress mediators. Cytokine 2016; 88:144-153.
12. Amirshahrokhi K, Zohouri A. Carvedilol prevents pancreatic β-cell damage and the development of type 1 diabetes in mice by the inhibition of proinflammatory cytokines, NF-κB, COX-2, iNOS and oxidative stress. Cytokine 202; 138:155394.
13. Wang J, Ono K, Dickstein DL, Arrieta-Cruz I, Zhao W, Qian X, et al. Carvedilol as a potential novel agent for the treatment of Alzheimer’s disease. Neurobiol Aging 2011; 32:2321.
14. Naidu PS, Singh A, Kulkarni SK. Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible anti-oxidant mechanisms. Br J Pharmacol 2002; 136:193-200.
15. Areti A, Komirishetty P, Kumar A. Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy. Toxicol Appl Pharmacol 2017; 322:97-103.
16. Savitz SI, Erhardt JA, Anthony JV, Gupta G, Li X, Barone FC, et al. The novel beta-blocker, carvedilol, provides neuroprotection in transient focal stroke. J Cereb Blood Flow Metab 2000; 20:1197-1204.
17. Yue TL, Lysko PG, Barone FC, Gu JL, Ruffolo RR Jr, Feuerstein GZ. Carvedilol, a new antihypertensive drug with unique antioxidant activity: potential role in cerebroprotection. Ann N Y Acad Sci 1994; 738:230-242.
18. Tasset I, Espínola C, Medina FJ, Feijóo M, Ruiz C, Moreno E, et al. Neuroprotective effect of carvedilol and melatonin on 3-nitropropionic acid-induced neurotoxicity in neuroblastoma. J Physiol Biochem 2009; 65:291-296.
19. Gao X, Wu B, Fu Z, Zhang Z, Xu G. Carvedilol abrogates hypoxia-induced oxidative stress and neuroinflammation in microglial BV2 cells. Eur J Pharmacol. 2017; 814:144-150.
20. LoPachin RM. Acrylamide Neurotoxicity: Neurological, morhological and molecular endpoints in animal models. Adv Exp Med Biol 2005; 561:21-37.
21. Zhang L, Gavin T, Barber DS, LoPachin RM. Role of the Nrf2-ARE pathway in acrylamide neurotoxicity. Toxicol Lett 2011; 205:1– 7.
22. Amirshahrokhi K. Thalidomide reduces glycerol-induced acute kidney injury by inhibition of NF-κB, NLRP3 inflammasome, COX-2 and inflammatory cytokines. Cytokine 2021; 144:155574.
23. Amirshahrokhi K, Khalili AR. Methylsulfonylmethane is effective against gastric mucosal injury. Eur J Pharmacol 2017; 811:240-248.
24. Yao X, Yan L, Yao L, Guan W, Zeng F, Cao F, et al. Acrylamide exposure impairs blood-cerebrospinal fluid barrier function. Neural Regen Res 2014; 9:555-560.
25. Triningsih D, Yang J-H, Sim KH, Lee C, Lee YJ. Acrylamide and its metabolite induce neurotoxicity via modulation of protein kinase C and AMP-activated protein kinase pathways. Toxicol in Vitro 2021;72:105105.
26. Farouk SM, Gad FA, Almeer R, Abdel-Daim MM, Emam MA. Exploring the possible neuroprotective and anti-oxidant potency of lycopene against acrylamide-induced neurotoxicity in rats’ brain. Biomed and Pharmacother 2021; 138:111458.
27. 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.
28. Song G, Liu Z, Liu Q, Liu X. Lipoic acid prevents acrylamide-induced neurotoxicity in CD-1 mice and BV2 microglial cells via maintaining redox homeostasis. J Funct Foods 2017; 35:363–375.
29. Kabel AM, Salama SA, Alghorabi AA, Estfanous RS. Amelioration of cyclosporine-induced testicular toxicity by carvedilol and/or alpha-lipoic acid: Role of TGF-β1, the proinflammatory cytokines, Nrf2/HO-1 pathway and apoptosis. Clin Exp Pharmacol Physiol 2020:47:1169-1181.
30. Refaie MMM, El-Hussieny M, Bayoumi AMA, Shehata S. Mechanisms mediating the cardioprotective effect of carvedilol in cadmium induced cardiotoxicity. Role of eNOS and HO1/Nrf2 pathway. Environ Toxicol Pharmacol 2019; 70:103198.
31. Ouyang Y, Chen Z, Tan M, Liu A, Chen M, Liu J, et al. Carvedilol, a third-generation β-blocker prevents oxidative stress-induced neuronal death and activates Nrf2/ARE pathway in HT22 cells. Biochem Biophys Res Commun 2013; 441; 917-922.
32. Wang L, Wang R, Jin M, Huang Y, Liu A, Qin J, et al. Carvedilol attenuates 6-hydroxydopamine-induced cell death in PC12 cells: Involvement of Akt and Nrf2/ARE pathways. Neurochem Res 2014; 39:1733-1740.
33. Santhanasabapathy R, Vasudevan S, Anupriya K, Pabitha R, Sudhandiran G. Farnesol quells oxidative stress, reactive gliosis and inflammation during acrylamide-induced neurotoxicity: Behavioral and biochemical evidence. Neuroscience 2015; 308:212-227.
34. Sharma C, Kang SC. Garcinol pacifies acrylamide induced cognitive impairments, neuroinflammation and neuronal apoptosis by modulating GSK signaling and activation of pCREB by regulating cathepsin B in the brain of zebrafish larvae. Food Chem Toxicol 2020; 138:111246.
35. Chen S, Chen H, Du Q, Shen J. Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing brain ischemia injury: Potential application of natural compounds. Front Physiol 2020; 11:433.
36. Maki RA, Holzer M, Motamedchaboki K, Malle E, Masliah E, et al. Human myeloperoxidase (hMPO) is expressed in neurons in the substantia nigra in Parkinson’s disease and in the hMPO-α-synuclein-A53T mouse model, correlating with increased nitration and aggregation of α-synuclein and exacerbation of motor impairment. Free Radic Biol Med 2019; 141:115-140. 
37. Alturfan AA, Tozan-Beceren A, Sehirli AO, Demiralp E, Sener G, Omurtag GZ. Resveratrol ameliorates oxidative DNA damage and protects against acrylamide-induced oxidative stress in rats. Mol Biol Rep 2012; 39:4589-4596.
38. Zhang L, Wang E, Chen F, Yan H, Yuan Y. Potential protective effects of oral administration of allicin on acrylamide-induced toxicity in male mice. Food and Funct 2013; 4;1229-1236.
39. Pan X, Wu X, Yan D, Peng C, Rao C, Yan H. Acrylamide-induced oxidative stress and inflammatory response are alleviated by N-acetylcysteine in PC12 cells: Involvement of the crosstalk between Nrf2 and NF-κB pathways regulated by MAPKs. Toxicol Lett 2018; 288:55-64.
40. Yan D, Pan X, Yao J, Wang D, Wu X, Chen X, et al. MAPKs and NF-κB-mediated acrylamide-induced neuropathy in rat striatum and human neuroblastoma cells SY5Y. J Cell Biochem 2019; 120:3898-3910.
41. Clemens JA. Cerebral ischemia: gene activation, neuronal injury, and the protective role of anti-oxidants. Free Radic Biol Med 2000; 28:1526-1531.
42. Kucukler S, Caglayan C, Darendelioğlu E, Kandemir FM. Morin attenuates acrylamide-induced testicular toxicity in rats by regulating the NF-κB, Bax/Bcl-2 and PI3K/Akt/mTOR signaling pathways. Life Sci 2020; 261,118301.
43. Pozniak PD, White MK, Khalili K. TNF-α/NF-κB signaling in the CNS: possible connection to EPHB2. J Neuroimmune Pharmacol 2014; 9:133-141.
44. Chen JH, Yang CH, Wang YS, Lee JG, Cheng CH, Chou CC. Acrylamide-induced mitochondria collapse and apoptosis in human astrocytoma cells. Food Chem Toxicol 2013; 51:446-452 
45. 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 2018; 43:595-601.
46. Li SX, Cui N, Zhang CL, Zhao XL, Yu SF, Xie KQ. Effect of subchronic exposure to acrylamide induced on the expression of bcl-2, bax and caspase-3 in the rat nervous system. Toxicology 2006; 217;46-53
47. Pan X, Yan D, Wang D, Wu X, Zhao W, Lu Q, et al. Mitochondrion-mediated apoptosis induced by acrylamide is regulated by a balance between Nrf2 anti-oxidant and MAPK signaling pathways in PC12 cells. Mol Neurobiol 2017; 54:4781-4794.
48. Liu J, Wang M. Carvedilol protection against endogenous Aβ-induced neurotoxicity in N2a cells. Cell Stress Chaperones 2018; 23:695-702.
49. Chen YL, Chung SY, Chai HT, Chen CH, Liu CF, Chen YL, et al. Early administration of carvedilol protected against doxorubicin-induced cardiomyopathy. J Pharmacol Exp Ther 2015; 355:516-527.
50. Dandona P, Ghanim H, Brooks DP. Anti-oxidant activity of carvedilol in cardiovascular disease. J Hypertens. 2007; 25:731-741.
51. Sahu BD, Koneru M, Bijargi SR, Kota A, Sistla R. Chromium-induced nephrotoxicity and ameliorative effect of carvedilol in rats: Involvement of oxidative stress, apoptosis and inflammation. Chem Biol Interact 2014; 223:69-79.