Zingerone attenuates sciatic nerve damage caused by sodium arsenite by inhibiting NF-κB, Caspase-3, and ATF-6/CHOP pathways and activating the Akt2/FOXO1 pathway

Document Type : Original Article

Authors

1 Department of Orthopedics and Traumatology, Faculty of Medicine, Kütahya Health Sciences University, Kütahya, Turkey

2 Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey

3 Department of Histology and Embryology, Faculty of Medicine, Aksaray University, Aksaray, Turkey

4 Department of Medical Biochemistry, Faculty of Medicine, Aksaray University, Aksaray, Turkey

Abstract

Objective(s): In the present study, the potential protective effects of zingerone (ZNG) against sciatic nerve damage caused by sodium arsenite (SA), a common environmental pollutant, were evaluated by various biochemical, molecular, and histological methods.
Materials and Methods: In the study, SA and ZNG were given to 35 male Sprague Dawley rats for 14 days. At the end of the period, the sciatic nerve tissues were taken and the markers involved in oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis were analyzed.
Results: The data obtained showed that SA decreased glutathione (GSH) levels and increased malondialdehyde (MDA) levels in the sciatic nerve tissue. However, it was determined that these markers approached the control group levels due to the anti-oxidant properties of ZNG. While SA triggered endoplasmic reticulum stress and apoptosis pathways, ZNG suppressed them. Moreover, SA up-regulated inflammatory markers such as nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), and neuronal nitric oxide synthases (nNOS) in the sciatic nerves and caused neuro-inflammation and inhibited cell survival by suppressing serine/threonine-protein kinase 2 (Akt2) and forkhead box protein O1 (FOXO1) genes. It has also been shown histopathologically that SA causes degeneration in the sciatic nerves. In contrast, ZNG suppressed neuro-inflammation, activated Akt2/FOXO1 signaling, and repaired histological irregularities.
Conclusion: In general, SA caused oxidative stress, inflammation, ER stress, and apoptosis in the sciatic nerves of rats, causing damage to the tissues, however, ZNG suppressed these pathways and protected the sciatic nerves from the destructive effect of SA.

Keywords

Main Subjects

References

1. Goudarzi M, Amiri S, Nesari A, Hosseinzadeh A, Mansouri E, Mehrzadi S. The possible neuroprotective effect of ellagic acid on sodium arsenate-induced neurotoxicity in rats. Life Sci 2018; 198:38-45.
2. Zarazúa S, Ríos R, Delgado JM, Santoyo ME, Ortiz-Pérez D, Jiménez-Capdeville ME. Decreased arginine methylation and myelin alterations in arsenic exposed rats. Neurotoxicology 2010; 31:94-100.
3. García-Chávez E, Jiménez I, Segura B, Del Razo LM. Lipid oxidative damage and distribution of inorganic arsenic and its metabolites in the rat nervous system after arsenite exposure: influence of alpha tocopherol supplementation. Neurotoxicology 2006; 27:1024-1031.
4. Akaras N, Gur C, Kucukler S, Kandemir FM. Zingerone reduces sodium arsenite-induced nephrotoxicity by regulating oxidative stress, inflammation, apoptosis and histopathological changes. Chem Biol Interact 2023; 374:110410.
5. Vahidnia A, Romijn F, Tiller M, Van Der Voet G, De Wolff F. Arsenic-induced toxicity: Effect on protein composition in sciatic nerve. Hum Exp Toxicol 2006; 25:667-674.
6. Frankel S, Concannon J, Brusky K, Pietrowicz E, Giorgianni S, Thompson WD, et al. Arsenic exposure disrupts neurite growth and complexity in vitro. Neurotoxicology 2009; 30:529-537.
7. He Q, Chen B, Chen S, Zhang M, Duan L, Feng X, et al. MBP‐activated autoimmunity plays a role in arsenic‐induced peripheral neuropathy and the potential protective effect of mecobalamin. Environ Toxicol 2021; 36:1243-1253.
8. Chou Y, Chao P, Tsai M, Cheng H, Chen K, Yang D, et al. Arsenite-induced cytotoxicity in dorsal root ganglion explants. Free Radic Biol Med 2008; 44:1553-1561.
9. Goebel HH, Schmidt PF, Bohl J, Tettenborn B, Krämer G, Gutmann L. Polyneuropathy due to acute arsenic intoxication: Biopsy studies. J Neuropathol Exp Neurol 1990; 49:137-149.
10. Gherardi RK, Chariot P, Vanderstigel M, Malapert D, Verroust J, Astier A, et al. Organic arsenic‐induced Guillain‐Barre‐like syndrome due to melarsoprol: A clinical, electrophysiological, and pathological study. Muscle Nerve 1990; 13:637-645.
11. Vaibhav K, Shrivastava P, Tabassum R, Khan A, Javed H, Ahmed ME, et al. Delayed administration of zingerone mitigates the behavioral and histological alteration via repression of oxidative stress and intrinsic programmed cell death in focal transient ischemic rats. Pharm Biochem Behav 2013; 113:53-62.
12. Borgonetti V, Governa P, Biagi M, Pellati F, Galeotti N. Zingiber officinale Roscoe rhizome extract alleviates neuropathic pain by inhibiting neuroinflammation in mice. Phytomedicine 2020; 78:153307.
13. Alam MF, Hijri SI, Alshahrani S, Alqahtani SS, Jali AM, Ahmed RA, et al. Zingerone attenuates carfilzomib-induced cardiotoxicity in rats through oxidative stress and inflammatory cytokine network. Int J Mol Sci 2022; 23:15617-15627.
14. Kuzu M, Kandemir FM, Yıldırım S, Çağlayan C, Küçükler S. Attenuation of sodium arsenite-induced cardiotoxicity and neurotoxicity with the antioxidant, anti-inflammatory, and antiapoptotic effects of hesperidin. Environ Sci Pollut Res 2021; 28:10818-10831.
15. Kucukler S, Darendelioğlu E, Caglayan C, Ayna A, Yıldırım S, Kandemir FM. Zingerone attenuates vancomycin-induced hepatotoxicity in rats through regulation of oxidative stress, inflammation and apoptosis. Life Sci 2020; 259:118382.
16. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 1966; 16:359-364.
17. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 1968; 25:192-205.
18. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 2001; 25:402-408.
19. Mallet M-L, Hadjivassiliou M, Sarrigiannis PG, Zis P. The role of oxidative stress in peripheral neuropathy. J Mol Neurosci 2020; 70:1009-1017.
20. Yardim A, Gur C, Comakli S, Ozdemir S, Kucukler S, Celik H, et al. Investigation of the effects of berberine on bortezomib-induced sciatic nerve and spinal cord damage in rats through pathways involved in oxidative stress and neuro-inflammation. Neurotoxicology 2022; 89:127-139.
21. Areti A, Yerra VG, Naidu V, Kumar A. Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy. Redox Biol 2014; 2:289-295.
22. Lin AM, Chao P, Fang S, Chi C, Yang C. Endoplasmic reticulum stress is involved in arsenite-induced oxidative injury in rat brain. Toxicol Appl Pharmacol 2007; 224:138-146.
23. Lin AM, Fang S, Chao P, Yang C. Melatonin attenuates arsenite‐induced apoptosis in rat brain: involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of α‐synuclein. J Pineal Res 2007; 43:163-171.
24. Semis HS, Gur C, Ileriturk M, Kandemir FM, Kaynar O. Evaluation of therapeutic effects of quercetin against achilles tendinopathy in rats via oxidative stress, inflammation, apoptosis, autophagy, and metalloproteinases. Am J Sports Med 2022; 50:486-498.
25. Yıldız MO, Çelik H, Caglayan C, Kandemir FM, Gür C, Bayav İ, et al. Neuromodulatory effects of hesperidin against sodium fluoride-induced neurotoxicity in rats: Involvement of neuroinflammation, endoplasmic reticulum stress, apoptosis and autophagy. Neurotoxicology 2022; 90:197-204.
26. Kandemir FM, Ileriturk M, Gur C. Rutin protects rat liver and kidney from sodium valproate-induce damage by attenuating oxidative stress, ER stress, inflammation, apoptosis and autophagy. Mol Biol Rep 2022; 49:6063-6074.
27. Yesildag K, Gur C, Ileriturk M, Kandemir FM. Evaluation of oxidative stress, inflammation, apoptosis, oxidative DNA damage and metalloproteinases in the lungs of rats treated with cadmium and carvacrol. Mol Biol Rep 2022:1-11.
28. Gur C, Kandemir O, Kandemir FM. Investigation of the effects of hesperidin administration on abamectin‐induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2/STAT3 pathways. Environ Toxicol 2022; 37:401-412.
29. Gur C, Kandemir FM, Darendelioglu E, Caglayan C, Kucukler S, Kandemir O, et al. Morin protects against acrylamide-induced neurotoxicity in rats: An investigation into different signal pathways. Environ Sci Pollut Res 2021; 28:49808-49819.
30. Gur C, Kandemir FM. Molecular and biochemical investigation of the protective effects of rutin against liver and kidney toxicity caused by malathion administration in a rat model. Environ Toxicol 2023; 38:555-565.
31. Caglayan C, Kandemir FM, Ayna A, Gür C, Küçükler S, Darendelioğlu E. Neuroprotective effects of 18β-glycyrrhetinic acid against bisphenol A-induced neurotoxicity in rats: involvement of neuronal apoptosis, endoplasmic reticulum stress and JAK1/STAT1 signaling pathway. Metab Brain Dis 2022; 37:1931-1940.
32. Goel Y, Fouda R, Gupta K. Endoplasmic reticulum stress in chemotherapy-induced peripheral neuropathy: Emerging role of phytochemicals. Antioxidants 2022; 11:265-282.
33. Semis HS, Kandemir FM, Kaynar O, Dogan T, Arikan SM. The protective effects of hesperidin against paclitaxel-induced peripheral neuropathy in rats. Life Sci 2021; 287:120104.
34. Lindholm D, Korhonen L, Eriksson O, Kõks S. Recent insights into the role of unfolded protein response in ER stress in health and disease. Front Cell Dev Biol 2017; 5:48-63.
35. D’arcy MS. Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019; 43:582-592.
36. Lin AM, Feng S, Chao P, Yang C-H. Melatonin inhibits arsenite‐induced peripheral neurotoxicity. J Pineal Res 2009; 46:64-70.
37. Celik H, Kucukler S, Ozdemir S, Comakli S, Gur C, Kandemir FM, et al. Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats. Neurotoxicology 2020; 80:29-40.
38. Sun H, Yang Y, Shao H, Sun W, Gu M, Wang H, et al. Sodium arsenite-induced learning and memory impairment is associated with endoplasmic reticulum stress-mediated apoptosis in rat hippocampus. Front Mol Neurosci 2017; 10:286-299.
39. Kim S-H, Oh S-H. Sodium arsenite-induced cytotoxicity is regulated by BNIP3L/Nix-mediated endoplasmic reticulum stress responses and CCPG1-mediated endoplasmic reticulum-phagy. Environ Toxicol Pharmacol 2023:104111.
40. Varışlı B, Caglayan C, Kandemir FM, Gür C, Ayna A, Genç A, et al. Chrysin mitigates diclofenac-induced hepatotoxicity by modulating oxidative stress, apoptosis, autophagy and endoplasmic reticulum stress in rats. Mol Biol Rep 2023; 50:433-442.
41. Kızıl HE, Gür C, Ayna A, Darendelioğlu E, Küçükler S, Sağ S. Contribution of oxidative stress, apoptosis, endoplasmic reticulum stress and autophagy pathways to the ameliorative effects of hesperidin in naf‐induced testicular toxicity. Chem  Biodiver 2023:e202200982.
42. Huang Z-Z, Li D, Liu C-C, Cui Y, Zhu H-Q, Zhang W-W, et al. CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. Brain Behav Immun 2014; 40:155-165.
43. Gur C, Kandemir FM, Caglayan C, Satıcı E. Chemopreventive effects of hesperidin against paclitaxel-induced hepatotoxicity and nephrotoxicity via amendment of Nrf2/HO-1 and caspase-3/Bax/Bcl-2 signaling pathways. Chem Biol Interact 2022; 365:110073.
44. Das J, Ghosh J, Manna P, Sil PC. Protective role of taurine against arsenic-induced mitochondria-dependent hepatic apoptosis via the inhibition of PKCδ-JNK pathway. PloS One 2010; 5:e12602-12620.
45. Li Z, Liu Y, Wang F, Gao Z, Elhefny MA, Habotta OA, et al. Neuroprotective effects of protocatechuic acid on sodium arsenate induced toxicity in mice: Role of oxidative stress, inflammation, and apoptosis. Chem Biol Interact 2021; 337:109392.
46. Jiang S-P, Zhang Z-D, Kang L-M, Wang Q-H, Zhang L, Chen H-P. Celecoxib reverts oxaliplatin-induced neuropathic pain through inhibiting PI3K/Akt2 pathway in the mouse dorsal root ganglion. Exp Neurol 2016; 275:11-16.
47. Yardim A, Kandemir FM, Ozdemir S, Kucukler S, Comakli S, Gur C, et al. Quercetin provides protection against the peripheral nerve damage caused by vincristine in rats by suppressing caspase 3, NF-κB, ATF-6 pathways and activating Nrf2, Akt pathways. Neurotoxicology 2020; 81:137-146.
48. Brand Y, Levano S, Radojevic V, Naldi AM, Setz C, Ryan AF, et al. All Akt isoforms (Akt1, Akt2, Akt3) are involved in normal hearing, but only Akt2 and Akt3 are involved in auditory hair cell survival in the mammalian inner ear. PloS One 2015; 10:e0121599.
49. Green BD, Jabbour AM, Sandow JJ, Riffkin CD, Masouras D, Daunt CP, et al. Akt1 is the principal Akt isoform regulating apoptosis in limiting cytokine concentrations. Cell Death  Differ 2013; 20:1341-1349.
50. Jung SY, Kim DY, Yune TY, Shin DH, Baek SB, Kim CJ. Treadmill exercise reduces spinal cord injury‑induced apoptosis by activating the PI3K/Akt pathway in rats. Exp Ther Med 2014; 7:587-593.
51. Park H-YL, Kim JH, Park CK. Neuronal cell death in the inner retina and the influence of vascular endothelial growth factor inhibition in a diabetic rat model. Am J Pathol 2014; 184:1752-1762.
52. Wang Y, Zhao Y, Sun C, Hu W, Zhao J, Li G, et al. Chitosan degradation products promote nerve regeneration by stimulating schwann cell proliferation via miR-27a/FOXO1 axis. Mol Neurobiol 2016; 53:28-39.
53. Singh G, Singh A, Singh P, Bhatti R. Bergapten ameliorates vincristine-induced peripheral neuropathy by inhibition of inflammatory cytokines and NFκB signaling. ACS Chem Neurosci 2019; 10:3008-3017.
54. Semis HS, Gur C, Ileriturk M, Kaynar O, Kandemir FM. Investigation of the anti-inflammatory effects of caffeic acid phenethyl ester in a model of λ-Carrageenan-induced paw edema in rats. Hum Exp Toxicol 2021; 40:S721-S738.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 4
April 2024
Pages 485-491

Files

Share

How to cite

Statistics