open access

Vol 77, No 2 (2018)
ORIGINAL ARTICLES
Published online: 2017-10-17
Submitted: 2017-08-04
Accepted: 2017-09-17
Get Citation

N-acetylcysteine versus progesterone on the cisplatin-induced peripheral neurotoxicity

S.M. Zaki, E.A. Mohamed, A.G. Motawie, S. Abdel Fattah
DOI: 10.5603/FM.a2017.0090
·
Pubmed: 29064553
·
Folia Morphol 2018;77(2):234-245.

open access

Vol 77, No 2 (2018)
ORIGINAL ARTICLES
Published online: 2017-10-17
Submitted: 2017-08-04
Accepted: 2017-09-17

Abstract

Background: Cisplatin-induced peripheral nerve neurotoxicity (CIPN) is the main obstacle in cisplatin treatment. The aim of this study was to compare the modulatory effects of N-acetylcysteine (NAC) and progesterone on CIPN, because there are scarce literature data on the protective effect of the proge­sterone on the CIPN.

Materials and methods: Twenty-four rats were divided into four groups: control, cisplatin-treated, concomitant cisplatin-treated and NAC-treated, and concomitant cisplatin-treated and progesterone-treated. Electron microscopic, immunohistochemical, real time polymerase chain reaction and histomorphome­tric analysis; oxidative/antioxidative markers (MDA/GSH and SOD), neurotoxic/ neuroprotective markers (iNOS/nNOS), inflammatory mediators (TNF-a and NF-kB) and BAX were done.

Results: The myelin sheath in the cisplatin-treated group elucidated infolding. The myelin was disfigured, degenerated, and extensively split with areas of focal loss. The axoplasm was atrophic. Ballooning and vacuolations of the mitochon­dria with alterations of Remak bundles structures were observed. Fewer of these changes were noted in the NAC and progesterone-treated groups. Decrease of the antioxidant SOD and GSH (81% and 64%) and increase of the oxidant MDA (9 folds), increment of the neurotoxic iNOS (1.9 folds) and decrement of the neuroprotective nNOS (64%) and elevation of the inflammatory mediators’ TNF-a and NF-kB (8.3 and 11 folds) in the cisplatin-treated group. Increase of the antioxidant SOD (1.3 and 2.5 folds) and GSH (120% and 79%) and decrease of the oxidant MDA (69% and 88%), decrement of the neurotoxic iNOS (56% and 68%) and increment of the neuroprotective nNOS (1.6 and one folds) and elevation of the inflammatory mediators’ TNF-a and NF-kB were observed in the NAC and progesterone-treated groups, respectively.

Conclusions: The toxic effect of CIPN might be attributed to either oxidative or severe inflammatory stress. Progesterone is efficient in ameliorating these effects; however, NAC is better. (Folia Morphol 2018; 77, 2: 234–245)

Abstract

Background: Cisplatin-induced peripheral nerve neurotoxicity (CIPN) is the main obstacle in cisplatin treatment. The aim of this study was to compare the modulatory effects of N-acetylcysteine (NAC) and progesterone on CIPN, because there are scarce literature data on the protective effect of the proge­sterone on the CIPN.

Materials and methods: Twenty-four rats were divided into four groups: control, cisplatin-treated, concomitant cisplatin-treated and NAC-treated, and concomitant cisplatin-treated and progesterone-treated. Electron microscopic, immunohistochemical, real time polymerase chain reaction and histomorphome­tric analysis; oxidative/antioxidative markers (MDA/GSH and SOD), neurotoxic/ neuroprotective markers (iNOS/nNOS), inflammatory mediators (TNF-a and NF-kB) and BAX were done.

Results: The myelin sheath in the cisplatin-treated group elucidated infolding. The myelin was disfigured, degenerated, and extensively split with areas of focal loss. The axoplasm was atrophic. Ballooning and vacuolations of the mitochon­dria with alterations of Remak bundles structures were observed. Fewer of these changes were noted in the NAC and progesterone-treated groups. Decrease of the antioxidant SOD and GSH (81% and 64%) and increase of the oxidant MDA (9 folds), increment of the neurotoxic iNOS (1.9 folds) and decrement of the neuroprotective nNOS (64%) and elevation of the inflammatory mediators’ TNF-a and NF-kB (8.3 and 11 folds) in the cisplatin-treated group. Increase of the antioxidant SOD (1.3 and 2.5 folds) and GSH (120% and 79%) and decrease of the oxidant MDA (69% and 88%), decrement of the neurotoxic iNOS (56% and 68%) and increment of the neuroprotective nNOS (1.6 and one folds) and elevation of the inflammatory mediators’ TNF-a and NF-kB were observed in the NAC and progesterone-treated groups, respectively.

Conclusions: The toxic effect of CIPN might be attributed to either oxidative or severe inflammatory stress. Progesterone is efficient in ameliorating these effects; however, NAC is better. (Folia Morphol 2018; 77, 2: 234–245)

Get Citation

Keywords

N-acetylcysteine, progesterone, cisplatin-induced peripheral neurotoxicity

About this article
Title

N-acetylcysteine versus progesterone on the cisplatin-induced peripheral neurotoxicity

Journal

Folia Morphologica

Issue

Vol 77, No 2 (2018)

Pages

234-245

Published online

2017-10-17

DOI

10.5603/FM.a2017.0090

Pubmed

29064553

Bibliographic record

Folia Morphol 2018;77(2):234-245.

Keywords

N-acetylcysteine
progesterone
cisplatin-induced peripheral neurotoxicity

Authors

S.M. Zaki
E.A. Mohamed
A.G. Motawie
S. Abdel Fattah

References (55)
  1. Abdel-Wahab WM, Moussa FI, Saad NA. Synergistic protective effect of -acetylcysteine and taurine against cisplatin-induced nephrotoxicity in rats. Drug Des Devel Ther. 2017; 11: 901–908.
  2. Akman T, Akman L, Erbas O, et al. The preventive effect of oxytocin to Cisplatin-induced neurotoxicity: an experimental rat model. Biomed Res Int. 2015; 2015: 167235.
  3. Andrabi SS, Parvez S, Tabassum H. Progesterone induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in rats. Dis Model Mech. 2017; 10(6): 787–796.
  4. Argyriou AA, Bruna J, Marmiroli P, et al. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol. 2012; 82(1): 51–77.
  5. Balayssac D, Ferrier J, Descoeur J, et al. Chemotherapy-induced peripheral neuropathies: from clinical relevance to preclinical evidence. Expert Opin Drug Saf. 2011; 10(3): 407–417.
  6. Birben E, Sahiner UM, Sackesen C, et al. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012; 5(1): 9–19.
  7. Bobylev I, Joshi AR, Barham M, et al. Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy. Mol Neurobiol. 2018; 55(2): 1227–1235.
  8. Boje KMK. Nitric oxide neurotoxicity in neurodegenerative diseases. Front Biosci. 2004; 9: 763–776.
  9. Carozzi VA, Marmiroli P, Cavaletti G. The role of oxidative stress and anti-oxidant treatment in platinum-induced peripheral neurotoxicity. Curr Cancer Drug Targets. 2010; 10(7): 670–682.
  10. Choi YM, Kim HK, Shim W, et al. Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation. PLoS One. 2015; 10(8): e0135083.
  11. Dableh LJ, Henry JL. Progesterone prevents development of neuropathic pain in a rat model: Timing and duration of treatment are critical. J Pain Res. 2011; 4: 91–101.
  12. Dawson VL, Dawson TM. Deadly conversations: nuclear-mitochondrial cross-talk. J Bioenerg Biomembr. 2004; 36(4): 287–294.
  13. de Pinto MC, Tommasi F, De Gara L. Changes in the antioxidant systems as part of the signaling pathway responsible for the programmed cell death activated by nitric oxide and reactive oxygen species in tobacco Bright-Yellow 2 cells. Plant Physiol. 2002; 130(2): 698–708.
  14. Dickey DT, Muldoon LL, Doolittle ND, et al. Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models. Cancer Chemother Pharmacol. 2008; 62(2): 235–241.
  15. Drew PD, Chavis JA. Female sex steroids: effects upon microglial cell activation. J Neuroimmunol. 2000; 111(1-2): 77–85.
  16. Englander EW. DNA damage response in peripheral nervous system: coping with cancer therapy-induced DNA lesions. DNA Repair (Amst). 2013; 12(8): 685–690.
  17. Fang C, Bourdette D, Banker G. Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases. Mol Neurodegener. 2012; 7: 29.
  18. Farshid AA, Tamaddonfard E, Najafi S. Effects of histidine and n-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats. Drug Chem Toxicol. 2015; 38(4): 436–441.
  19. Galluzzi L, Vitale I, Michels J, et al. Systems biology of cisplatin resistance: past, present and future. Cell Death Dis. 2014; 5: e1257.
  20. George A, Buehl A, Sommer C. Wallerian degeneration after crush injury of rat sciatic nerve increases endo- and epineurial tumor necrosis factor-alpha protein. Neurosci Lett. 2004; 372(3): 215–219.
  21. Giordano S, Darley-Usmar V, Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol. 2014; 2: 82–90.
  22. Gonzalez Deniselle MC, López-Costa JJ, Saavedra JP, et al. Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease. Neurobiol Dis. 2002; 11(3): 457–468.
  23. Hart AM, Terenghi G, Wiberg M, et al. Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury. Neuroscience. 2004; 125(1): 91–101.
  24. Husain MA, Ishqi HM, Sarwar T, et al. Identification and expression analysis of alternatively spliced new transcript isoform of Bax gene in mouse. Gene. 2017; 621: 21–31.
  25. Jain KK. Drug-induced neurological disorders. 3rd rev. and expanded ed. Cambridge, MA: Hogrefe Pub.; 2012. X, 452.
  26. Kerksick C, Willoughby D. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr. 2005; 2: 38–44.
  27. Keswani SC, Bosch-Marcé M, Reed N, et al. Nitric oxide prevents axonal degeneration by inducing HIF-1-dependent expression of erythropoietin. Proc Natl Acad Sci U S A. 2011; 108(12): 4986–4990.
  28. Khan M, Sekhon B, Jatana M, et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res. 2004; 76(4): 519–527.
  29. Kim HJ, So HS, Lee JH, et al. Role of proinflammatory cytokines in cisplatin-induced vestibular hair cell damage. Head Neck. 2008; 30(11): 1445–1456.
  30. Kim SJ, Lim JY, Lee JNo, et al. Activation of β-catenin by inhibitors of glycogen synthase kinase-3 ameliorates cisplatin-induced cytotoxicity and pro-inflammatory cytokine expression in HEI-OC1 cells. Toxicology. 2014; 320: 74–82.
  31. Kobayashi M, To H, Yuzawa M, et al. Effects of dosing time and schedule on cisplatin-induced nephrotoxicity in rats. J Pharm Pharmacol. 2000; 52(10): 1233–1237.
  32. Lanté F, Meunier J, Guiramand J, et al. Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation. Hippocampus. 2008; 18(6): 602–609.
  33. Lappas M, Permezel M, Rice GE. N-Acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-kappaB deoxyribonucleic acid-binding activity in human fetal membranes in vitro. J Clin Endocrinol Metab. 2003; 88(4): 1723–1729.
  34. Lin H, Heo BHa, Yoon MHa. A New Rat Model of Cisplatin-induced Neuropathic Pain. Korean J Pain. 2015; 28(4): 236–243.
  35. Low PA, Nickander KK, Tritschler HJ. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Diabetes. 1997; 46(Supplement_2): S38–S42.
  36. Melli G, Taiana M, Camozzi F, et al. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol. 2008; 214(2): 276–284.
  37. Meyer A, Laverny G, Allenbach Y, et al. IFN-beta-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis. Acta Neuropathol. 2017; 134(4): 655–666.
  38. Moorthy K, Sharma D, Basir SF, et al. Administration of estradiol and progesterone modulate the activities of antioxidant enzyme and aminotransferases in naturally menopausal rats. Exp Gerontol. 2005; 40(4): 295–302.
  39. Owen JB, Butterfield DA. Measurement of oxidized/reduced glutathione ratio. Methods Mol Biol. 2010; 648: 269–277.
  40. Park HJ, Stokes JA, Pirie E, et al. Persistent hyperalgesia in the cisplatin-treated mouse as defined by threshold measures, the conditioned place preference paradigm, and changes in dorsal root ganglia activated transcription factor 3: the effects of gabapentin, ketorolac, and etanercept. Anesth Analg. 2013; 116(1): 224–231.
  41. Park HJ. Chemotherapy induced peripheral neuropathic pain. Korean J Anesthesiol. 2014; 67(1): 4–7.
  42. Phensy A, Driskill C, Lindquist K, et al. Antioxidant treatment in male mice prevents mitochondrial and synaptic changes in an NMDA receptor dysfunction model of schizophrenia. eNeuro. 2017; 4(4).
  43. Reid AJ, Shawcross SG, Hamilton AE, et al. N-acetylcysteine alters apoptotic gene expression in axotomised primary sensory afferent subpopulations. Neurosci Res. 2009; 65(2): 148–155.
  44. Roof RL, Duvdevani R, Braswell L, et al. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol. 1994; 129(1): 64–69.
  45. Roof RL, Duvdevani R, Heyburn JW, et al. Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Exp Neurol. 1996; 138(2): 246–251.
  46. Rybak LP, Kelly T. Ototoxicity: bioprotective mechanisms. Curr Opin Otolaryngol Head Neck Surg. 2003; 11(5): 328–333.
  47. Sahu BD, Kuncha M, Putcha UK, et al. Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation. Exp Toxicol Pathol. 2013; 65(6): 933–940.
  48. Sandireddy R, Yerra VG, Areti A, et al. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int J Endocrinol. 2014; 2014: 674987.
  49. Seto Y, Okazaki F, Horikawa K, et al. Influence of dosing times on cisplatin-induced peripheral neuropathy in rats. BMC Cancer. 2016; 16(1): 756.
  50. Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev. 2008; 57(2): 386–397.
  51. VanLandingham JW, Cekic M, Cutler S, et al. Neurosteroids reduce inflammation after TBI through CD55 induction. Neurosci Lett. 2007; 425(2): 94–98.
  52. Wang XM, Lehky TJ, Brell JM, et al. Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. Cytokine. 2012; 59(1): 3–9.
  53. Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther. 2005; 312(2): 424–431.
  54. Yang X, Fraser M, Moll UM, et al. Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res. 2006; 66(6): 3126–3136.
  55. Zhu J, Carozzi VA, Reed N, et al. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity. Sci Rep. 2016; 6: 28861.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By  "Via Medica sp. z o.o." sp.k., Świętokrzyska 73, 80–180 Gdańsk, Poland

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl