Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions


The purpose of the current study was to examine the neuroprotective effect of rutin against colistin-induced neurotoxicity in rats. Thirty-five male Sprague Dawley rats were randomly divided into 5 groups. The control group (orally received physiological saline), the rutin group (orally administered 100 mg/kg body weight), the colistin group (i.p. administered 15 mg/kg body weight), the Col + Rut 50 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 50 mg/kg body weight of rutin), the Col + Rut 100 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 100 mg/kg body weight of rutin). Administration of colistin increased levels of glial fibrillary acidic protein and brain-derived neurotrophic factor and acetylcholinesterase and butyrylcholinesterase activities while decreasing level of cyclic AMP response element binding protein and extracellular signal regulated kinases 1 and 2 (ERK1/2) expressions. Colistin increased oxidative impairments as evidenced by a decrease in level of nuclear factor erythroid 2-related factor 2 (Nrf-2), glutathione, superoxide dismutase, glutathione peroxidase and catalase activities, and increased malondialdehyde content. Colistin also increased the levels of the apoptotic and inflammatoric parameters such as cysteine aspartate specific protease-3 (caspase-3), p53, B-cell lymphoma-2 (Bcl-2), nuclear factor kappa B (NF-κB), Bcl-2 associated X protein (Bax), tumor necrosis factor-α (TNF-α) and neuronal nitric oxide synthase (nNOS). Rutin treatment restored the brain function by attenuating colistin-induced oxidative stress, apoptosis, inflammation, histopathological and immunohistochemical alteration suggesting that rutin supplementation mitigated colistin-induced neurotoxicity in male rats.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Wang J, Yi M, Chen X, Muhammad I, Liu F, Li R, Li J, Li J (2016) Effects of colistin on amino acid neurotransmitters and blood-brain barrier in the mouse brain. Neurotoxicol Teratol 55:32–37

  2. 2.

    Falagas ME, Kasiakou SK, Saravolatz LD (2005) Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 40(9):1333–1341

  3. 3.

    Aksu EH, Kandemir FM, Küçükler S, Mahamadu A (2018) Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin. J Biochem Mol Toxicol 32(11):e22201

  4. 4.

    Liu Y, Dai C, Gao R, Li J (2013) Ascorbic acid protects against colistin sulfate-induced neurotoxicity in PC12 cells. Toxicol Mech Methods 23(8):584–590

  5. 5.

    Hanedan B, Ozkaraca M, Kirbas A, Kandemir FM, Aktas MS, Kilic K, Comakli S, Kucukler S, Bilgili A (2018) Investigation of the effects of hesperidin and chrysin on renal injury induced by colistin in rats. Biomed Pharmacother 108:1607–1616

  6. 6.

    Ajiboye T (2018) Colistin sulphate induced neurotoxicity: studies on cholinergic, monoaminergic, purinergic and oxidative stress biomarkers. Biomed Pharmacother 103:1701–1707

  7. 7.

    Edrees NE, Galal AA, Monaem ARA, Beheiry RR, Metwally MM (2018) Curcumin alleviates colistin-induced nephrotoxicity and neurotoxicity in rats via attenuation of oxidative stress, inflammation and apoptosis. Chem-Biol Interact 294:56–64

  8. 8.

    Dai C, Li J, Lin W, Li G, Sun M, Wang F, Li J (2012) Electrophysiology and ultrastructural changes in mouse sciatic nerve associated with colistin sulfate exposure. Toxicol Mech Methods 22(8):592–596

  9. 9.

    Dai C, Li J, Li J (2013) New insight in colistin induced neurotoxicity with the mitochondrial dysfunction in mice central nervous tissues. Exp Toxicol Pathol 65(6):941–948

  10. 10.

    Panche A, Diwan A, Chandra S (2016) Flavonoids: an overview. J Nutr Sci. https://doi.org/10.1017/jns.2016.41

  11. 11.

    Kuzu M, Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Turk E (2018) Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. Biomed Pharmacother 106:443–453

  12. 12.

    Ola MS, Ahmed MM, Ahmad R, Abuohashish HM, Al-Rejaie SS, Alhomida AS (2015) Neuroprotective effects of rutin in streptozotocin-induced diabetic rat retina. J Mol Neurosci 56(2):440–448

  13. 13.

    Alhoshani AR, Hafez MM, Husain S, Al-sheikh AM, Alotaibi MR, Al Rejaie SS, Alshammari MA, Almutairi MM, Al-Shabanah OA (2017) Protective effect of rutin supplementation against cisplatin-induced nephrotoxicity in rats. BMC Nephrol 18(1):194

  14. 14.

    Aksu E, Kandemir F, Özkaraca M, Ömür A, Küçükler S, Çomaklı S (2017) Rutin ameliorates cisplatin-induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats. Andrologia 49(1):e12593

  15. 15.

    Almutairi MM, Alanazi WA, Alshammari MA, Alotaibi MR, Alhoshani AR, Al-Rejaie SS, Hafez MM, Al-Shabanah OA (2017) Neuro-protective effect of rutin against Cisplatin-induced neurotoxic rat model. BMC Complement Altern Med 17(1):472

  16. 16.

    Caglayan C, Kandemir FM, Darendelioğlu E, Yıldırım S, Kucukler S, Dortbudak MB (2019) Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. J Trace Elem Med Biol 56:60–68

  17. 17.

    Kandemir FM, Ozkaraca M, Yildirim BA, Hanedan B, Kirbas A, Kilic K, Aktas E, Benzer F (2015) Rutin attenuates gentamicin-induced renal damage by reducing oxidative stress, inflammation, apoptosis, and autophagy in rats. Ren Fail 37(3):518–525

  18. 18.

    Caglayan C, Kandemir FM, Yildirim S, Kucukler S, Eser G (2019) Rutin protects mercuric chloride-induced nephrotoxicity via targeting of aquaporin 1 level, oxidative stress, apoptosis and inflammation in rats. J Trace Elem Med Biol 54:69–78

  19. 19.

    Aebi H (1984) [13] Catalase in vitro. In: Packer L (ed) Methods in enzymology, vol 105, Elsevier, Amsterdam, pp 121–126

  20. 20.

    Matkovics B (1988) Determination of enzyme activity in lipid peroxidation and glutathione pathways. Laboratoriumi Diagnosztika 15:248–250

  21. 21.

    Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34(3):497–500

  22. 22.

    Placer ZA, Cushman LL, Johnson BC (1966) Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 16(2):359–364

  23. 23.

    Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 25:192–205

  24. 24.

    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

  25. 25.

    Ellman GL, Courtney KD, Andres V Jr, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–95

  26. 26.

    Kandemir FM, Yildirim S, Caglayan C, Kucukler S, Eser G (2019) Protective effects of zingerone on cisplatin-induced nephrotoxicity in female rats. Environ Sci Pollut Res 26:22562–22574

  27. 27.

    Özdemir S, Çomaklı S (2018) Investigation of the interaction between bta-miR-222 and the estrogen receptor alpha gene in the bovine ovarium. Reprod Biol 18(3):259–266

  28. 28.

    Arslan H, Altun S, Özdemir S (2017) Acute toxication of deltamethrin results in activation of iNOS, 8-OHdG and up-regulation of caspase 3, iNOS gene expression in common carp (Cyprinus carpio L.). Aquat Toxicol 187:90–99

  29. 29.

    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2ΔΔCT method. Methods 25(4):402–408

  30. 30.

    Dai C, Ciccotosto GD, Cappai R, Tang S, Li D, Xie S, Xiao X, Velkov T (2018) Curcumin attenuates colistin-induced neurotoxicity in N2a cells via anti-inflammatory activity, suppression of oxidative stress, and apoptosis. Mol Neurobiol 55(1):421–434

  31. 31.

    Benzer F, Kandemir FM, Kucukler S, Comaklı S, Caglayan C (2018) Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch Physiol Biochem 124(5):448–457

  32. 32.

    Dai C, Tang S, Deng S, Zhang S, Zhou Y, Velkov T, Li J, Xiao X (2015) Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway. Antimicrob Agents Chemother 59(1):579–585

  33. 33.

    Jiang G-Z, Li J-C (2014) Protective effects of ginsenoside Rg1 against colistin sulfate-induced neurotoxicity in PC12 cells. Cell Mol Neurobiol 34(2):167–172

  34. 34.

    Dai C, Tang S, Velkov T, Xiao X (2016) Colistin-induced apoptosis of neuroblastoma-2a cells involves the generation of reactive oxygen species, mitochondrial dysfunction, and autophagy. Mol Neurobiol 53(7):4685–4700

  35. 35.

    Dai C, Ciccotosto GD, Cappai R, Wang Y, Tang S, Hoyer D, Schneider EK, Velkov T, Xiao X (2017) Rapamycin confers neuroprotection against colistin-induced oxidative stress, mitochondria dysfunction, and apoptosis through the activation of autophagy and mTOR/Akt/CREB signaling pathways. ACS Chem Neurosci 9(4):824–837

  36. 36.

    Zeng J, Chen Y, Ding R, Feng L, Fu Z, Yang S, Deng X, Xie Z, Zheng S (2017) Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS-and/or NF-κB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway. J Neuroinflammation 14(1):119

  37. 37.

    Dai C, Li B, Zhou Y, Li D, Zhang S, Li H, Xiao X, Tang S (2016) Curcumin attenuates quinocetone induced apoptosis and inflammation via the opposite modulation of Nrf2/HO-1 and NF-kB pathway in human hepatocyte L02 cells. Food Chem Toxicol 95:52–63

  38. 38.

    Magalingam KB, Radhakrishnan A, Haleagrahara N (2013) Rutin, a bioflavonoid antioxidant protects rat pheochromocytoma (PC-12) cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Int J Mol Med 32(1):235–240

  39. 39.

    Akinyemi AJ, Oboh G, Fadaka AO, Olatunji BP, Akomolafe S (2017) Curcumin administration suppress acetylcholinesterase gene expression in cadmium treated rats. Neurotoxicology 62:75–79

  40. 40.

    Bayindir S, Caglayan C, Karaman M, Gülcin İ (2019) The green synthesis and molecular docking of novel N-substituted rhodanines as effective inhibitors for carbonic anhydrase and acetylcholinesterase enzymes. Bioorg Chem 90:103096

  41. 41.

    Maurice T, Strehaiano M, Siméon N, Bertrand C, Chatonnet A (2016) Learning performances and vulnerability to amyloid toxicity in the butyrylcholinesterase knockout mouse. Behav Brain Res 296:351–360

  42. 42.

    Taslimi P, Kandemir FM, Demir Y, İleritürk M, Temel Y, Caglayan C, Gulçin İ (2019) The antidiabetic and anticholinergic effects of chrysin on cyclophosphamide-induced multiple organ toxicity in rats: Pharmacological evaluation of some metabolic enzyme activities. J Biochem Mol Toxicol 33:e22313

  43. 43.

    Caglayan C (2019) The effects of naringin on different cyclophosphamide-induced organ toxicities in rats: investigation of changes in some metabolic enzyme activities. Environ Sci Pollut Res 26:26664–26673

  44. 44.

    Anesti M, Stavropoulou N, Atsopardi K, Lamari FN, Panagopoulos NT, Margarity M (2020) Effect of rutin on anxiety-like behavior and activity of acetylcholinesterase isoforms in specific brain regions of pentylenetetrazol-treated mice. Epilepsy Behav 102:106632

  45. 45.

    Yan X, Chen T, Zhang L, Du H (2018) Study of the interactions of forsythiaside and rutin with acetylcholinesterase (AChE). Int J Biol Macromol 119:1344–1352

  46. 46.

    Wu Y-Q, Dang R-L, Tang M-M, Cai H-L, Li H-D, Liao D-H, He X, Cao L-J, Xue Y, Jiang P (2016) Long chain omega-3 polyunsaturated fatty acid supplementation alleviates doxorubicin-induced depressive-like behaviors and neurotoxicity in rats: involvement of oxidative stress and neuroinflammation. Nutrients 8(4):243

  47. 47.

    Olmos G, Lladó J (2014) Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediators Inflamm 2014:861231

  48. 48.

    Kim YE, Hwang CJ, Lee HP, Kim CS, Son DJ, Ham YW, Hellström M, Han S-B, Kim HS, Park EK (2017) Inhibitory effect of punicalagin on lipopolysaccharide-induced neuroinflammation, oxidative stress and memory impairment via inhibition of nuclear factor-kappaB. Neuropharmacology 117:21–32

  49. 49.

    Caglayan C, Kandemir FM, Yıldırım S, Kucukler S, Kılınc MA, Saglam YS (2018) Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomed Pharmacother 102:517–530

  50. 50.

    Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB (2018) Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacother 105:981–991

  51. 51.

    Hu Z, Wang W, Ling J, Jiang C (2016) α-Mangostin inhibits α-synuclein-induced microglial neuroinflammation and neurotoxicity. Cell Mol Neurobiol 36(5):811–820

  52. 52.

    Çelik H, Kucukler S, Çomaklı S, Özdemir S, Caglayan C, Yardım A, Kandemir FM (2020) Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis. Neurotoxicology 76:126–137

  53. 53.

    Nkpaa KW, Onyeso GI (2018) Rutin attenuates neurobehavioral deficits, oxidative stress, neuro-inflammation and apoptosis in fluoride treated rats. Neurosci Lett 682:92–99

  54. 54.

    Cheng G, Kong Rh, Lm Z, Jn Z (2012) Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 167(4):699–719

  55. 55.

    Wu H-J, Pu J-L, Krafft PR, Zhang J-M, Chen S (2015) The molecular mechanisms between autophagy and apoptosis: potential role in central nervous system disorders. Cell Mol Neurobiol 35(1):85–99

  56. 56.

    Song K, Kim S, Na J-Y, Park J-H, Kim J-K, Kim J-H, Kwon J (2014) Rutin attenuates ethanol-induced neurotoxicity in hippocampal neuronal cells by increasing aldehyde dehydrogenase 2. Food Chem Toxicol 72:228–233

  57. 57.

    Cheng P, Alberts I, Li X (2013) The role of ERK1/2 in the regulation of proliferation and differentiation of astrocytes in developing brain. Int J Dev Neurosci 31(8):783–789

  58. 58.

    Zhang F, Wu Y, Jia J, Hu Y-S (2010) Pre-ischemic treadmill training induces tolerance to brain ischemia: involvement of glutamate and ERK1/2. Molecules 15(8):5246–5257

  59. 59.

    Tripathi S, Kushwaha R, Mishra J, Gupta MK, Kumar H, Sanyal S, Singh D, Sanyal S, Sahasrabuddhe AA, Kamthan M (2017) Docosahexaenoic acid up-regulates both PI 3K/AKT-dependent FABP 7–PPAR γ interaction and MKP 3 that enhance GFAP in developing rat brain astrocytes. J Neurochem 140(1):96–113

  60. 60.

    Hol EM, Pekny M (2015) Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol 32:121–130

  61. 61.

    Hu Y, Liu M-Y, Liu P, Dong X, Boran AD (2014) Neuroprotective effects of 3, 6′-disinapoyl sucrose through increased BDNF levels and CREB phosphorylation via the CaMKII and ERK1/2 pathway. J Mol Neurosci 53(4):600–607

  62. 62.

    Pláteník J, Fišar Z, Buchal R, Jirák R, Kitzlerová E, Zvěřová M, Raboch J (2014) GSK3β, CREB, and BDNF in peripheral blood of patients with Alzheimer's disease and depression. Prog Neuro-Psychopharmacol Biol Psychiatry 50:83–93

  63. 63.

    Moghbelinejad S, Nassiri-Asl M, Farivar TN, Abbasi E, Sheikhi M, Taghiloo M, Farsad F, Samimi A, Hajiali F (2014) Rutin activates the MAPK pathway and BDNF gene expression on beta-amyloid induced neurotoxicity in rats. Toxicol Lett 224(1):108–113

Download references


This work was supported by Grants from Private Buhara Hospital, Erzurum. Therefore, we are grateful to Dr. Serdar Kömeç on behalf of the Hospital.

Author information

Correspondence to Fatih Mehmet Kandemir or Cuneyt Caglayan.

Ethics declarations

Conflicts of interest

The authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Çelik, H., Kandemir, F.M., Caglayan, C. et al. Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions. Mol Biol Rep (2020). https://doi.org/10.1007/s11033-020-05302-z

Download citation


  • Apoptosis
  • Colistin
  • Inflammation
  • Oxidative stress
  • Neurotoxicity
  • Rutin