Selçuk YILMAZ, Hasan ŞİMŞEK, Sefa KÜÇÜKLER, Serpil AYGÖRMEZ, Ender ERDOĞAN, Fatih Mehmet KANDEMİR

Naringin is Protective in Paclitaxel-Induced Peripheral Neuropathy; A Multi-Biomarker Approach

Aim: Cancer is a disease that is on the rise worldwide. Paclitaxel (PTX) is one of the most common chemotherapeutic agents used in the treatment of many cancers. PTX causes toxic effects by increasing oxidative stress in tissues. Naringin is a powerful antioxidant found naturally in many plants, especially citrus fruits. The aim of this study was to determine the protective effects of NRG in PTX-induced sciatic nerve injury. Methods: Thirty-five male rats were randomly divided into five groups: control, PTX, NRG, PTX+NRG-50, PTX+NRG-100. PTX was administered i.p. for the first five days and NRG 50 or 100 mg/kg orally on days 6-14. Sciatic nerve tissues were harvested and analyzed for markers of oxidative stress, inflammation and apoptosis damage levels by biochemical methods. Results: PTX caused oxidative stress damage by increasing lipid peroxidation (MDA) and decreasing antioxidant capacity (SOD, CAT, GPx and GSH), inflammatory damage by increasing proinflammatory cytokine (NF-κB, TNF-α, IL-1β, SIRT1, TLR4, and NRF2) release, apoptotic damage by increasing apoptotic factor (Bax) and decreasing antiapoptotic factor (Bcl-2) in sciatic nerve tissue (p < 0.05). NRG, on the other hand, reversed all these changes in sciatic nerve tissue and reduced PTX-induced oxidative stress damage, inflammatory damage and apoptotic damage (p < 0.05). These effects were more effective at the 100 mg/kg dose of NRG than at the 50 mg/kg dose (p < 0.05). Conclusions: In sciatic nerve tissue, PTX induced peripheral neuropathy with increased oxidative stress, inflammation and apoptotic damage. NRG showed a protective effect against PTX-induced peripheral neuropathy.

Keywords:

Apoptosis, Naringin, Oxidative stress, Paclitaxel, Sciatic nerve,

PDF

___

1. Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021; 134(7):783-91.
2. Choudhury H, Maheshwari R, Pandey M, Tekade M, Gorain B, Tekade RK. Advanced nanoscale carrier-based approaches to overcome biopharmaceutical issues associated with anticancer drug 'Etoposide'. Mater Sci Eng C Mater Biol Appl. 2020; 106:110275.
3. 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.
4. Galley HF, McCormick B, Wilson KL, Lowes DA, Colvin L, Torsney C. Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat. J Pineal Res. 2017; 63(4):e12444.
5. Yardım A, Kandemir FM, Çomaklı S, et al. Protective Effects of Curcumin Against Paclitaxel-Induced Spinal Cord and Sciatic Nerve Injuries in Rats. Neurochem Res. 2021; 46(2):379-95.
6. Yang YH, Mao JW, Tan XL. Research progress on the source, production, and anti-cancer mechanisms of paclitaxel. Chin J Nat Med. 2020; 18(12):890-97.
7. Zhu L, Chen L. Progress in research on paclitaxel and tumor immunotherapy. Cell Mol Biol Lett. 2019; 24:40.
8. Klein I, Lehmann HC. Pathomechanisms of Paclitaxel-Induced Peripheral Neuropathy. Toxics. 2021; 9(10):229.
9. 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(6):1931-40.
10. Temel Y, Çağlayan C, Ahmed BM, Kandemir FM, Çiftci M. The effects of chrysin and naringin on cyclophosphamide-induced erythrocyte damage in rats: biochemical evaluation of some enzyme activities in vivo and in vitro. Naunyn Schmiedebergs Arch Pharmacol. 2021; 394(4):645-54.
11. Varışlı B, Caglayan C, Kandemir FM, et al. Chrysin mitigates diclofenac-induced hepatotoxicity by modulating oxidative stress, apoptosis, autophagy and endoplasmic reticulum stress in rats. Mol Biol Rep. 2023; 50(1):433-42.
12. Semis HS, Kandemir FM, Caglayan C, Kaynar O, Genc A, Arıkan SM. Protective effect of naringin against oxaliplatin-induced peripheral neuropathy in rats: A behavioral and molecular study. J Biochem Mol Toxicol. 2022; 36(9):e23121.
13. Şahin A, Sakat MS, Kılıç K, et al. The protective effect of Naringenin against ovalbumin-induced allergic rhinitis in rats. Eur Arch Otorhinolaryngol. 2021; 278(12):4839-46.
14. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem. 1966; 16(2):359-64.
15. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988; 34(3):497-500.
16. Aebi H. Catalase in vitro. Methods Enzymol. 1984; 105:121-26.
17. Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976; 71(4):952-58.
18. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968; 25(1):192-205.
19. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75.
20. 20. Ileriturk M, Kandemir O, Akaras N, Simsek H, Genc A, Kandemir FM. Hesperidin has a protective effect on paclitaxel-induced testicular toxicity through regulating oxidative stress, apoptosis, inflammation and endoplasmic reticulum stress. Reprod Toxicol. 2023; 118:108369.
21. Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ. Therapeutic effects of silymarin and naringin on methotrexate‐induced nephrotoxicity in rats: Biochemical evaluation of anti‐inflammatory, antiapoptotic, and antiautophagic properties. J. Food Biochem. 2017; 41(5), e12398.
22. Caglayan C, Demir Y, Kucukler S, Taslimi P, Kandemir FM, Gulçin İ. The effects of hesperidin on sodium arsenite-induced different organ toxicity in rats on metabolic enzymes as antidiabetic and anticholinergics potentials: A biochemical approach. J Food Biochem. 2019; 43(2):e12720.
23. 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(3):401-12.
24. Akaras N. , Gür C. , Şimşek H. , Tuncer S. Ç. Effects of Quercetin on Cypermethrin-Induced Stomach Injury: The Role of Oxidative Stress, Inflammation, and Apoptosis. Gümüşhane Univ Sağlık bilim Derg. 2023; 12(2): 556-66.
25. Sagliyan A, Benzer F, Kandemir FM, Gunay C, Han MC, Ozkaraca M. Beneficial effects of oral administrations of grape seed extract on healing of surgically induced skin wounds in rabbits. Revue Méd Vét. 2012; 163(1):11-17.
26. Küçükler S, Kandemir FM, Yıldırım S. Protective effect of chrysin on indomethacin induced gastric ulcer in rats: role of multi-pathway regulation. Biotech Histochem. 2022; 97(7):490-503.
27. Şimşek H, Akaras N, Gür C, Küçükler S, Kandemir FM. Beneficial effects of Chrysin on Cadmium-induced nephrotoxicity in rats: Modulating the levels of Nrf2/HO-1, RAGE/NLRP3, and Caspase-3/Bax/Bcl-2 signaling pathways. Gene. 2023; 875:147502.
28. Akaras N, Abuc OO, Koc K, et al. (1 → 3)-β-d-glucan enhances the toxicity induced by Bortezomib in rat testis. J Food Biochem. 2020; 44(3):e13155.
29. Gur C, Akarsu SA, Akaras N, Tuncer SC, Kandemir FM. Carvacrol reduces abnormal and dead sperm counts by attenuating sodium arsenite-induced oxidative stress, inflammation, apoptosis, and autophagy in the testicular tissues of rats. Environ Toxicol. 2023; 38(6):1265-76.
30. Simsek H, Akaras N. Acacetin ameliorates acetylsalicylic acid-induced gastric ulcer in rats by interfering with oxidative stress, inflammation, and apoptosis. Int J Med Biochem 2023; 6(2):96-103.
31. 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.
32. Kocak C, Kocak FE, Akcilar R, et al. Molecular and biochemical evidence on the protective effects of embelin and carnosic acid in isoproterenol-induced acute myocardial injury in rats. Life Sci. 2016;147:15-23.
33. 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.
34. Zeren S, Bayhan Z, Kocak FE, et al. Gastroprotective effects of sulforaphane and thymoquinone against acetylsalicylic acid-induced gastric ulcer in rats. J Surg Res. 2016; 203(2):348-59.
35. Çomaklı S, Özdemir S, Küçükler S, Kandemir FM. Beneficial effects of quercetin on vincristine-induced liver injury in rats: Modulating the levels of Nrf2/HO-1, NF-kB/STAT3, and SIRT1/PGC-1α. J Biochem Mol Toxicol. 2023; 37(5):e23326.
36. Yardim A, Gur C, Comakli S, 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; 89:127-39.
37. Akcılar R, Akcılar A, Koçak C, et al. Effects of Ukrain on intestinal apoptosis caused by ischemia-reperfusion injury in rats. Int J Clin Exp Med. 2015; 8(12):22158-66.
38. Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res Int. 2018; 25(21):20968-84.
39. Akaras N, Bal T, Atilay H, Selli J, Halici MB. Protective effects of agomelatine on testicular damage caused by bortezomib. Biotech Histochem. 2017; 92(8):552-59.
40. 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.