Journal of Medical Toxicology

, Volume 9, Issue 1, pp 25–33 | Cite as

The Effect of Curcumin on Oxaliplatin and Cisplatin Neurotoxicity in Rats: Some Behavioral, Biochemical, and Histopathological Studies

  • Mansour S. Al Moundhri
  • Suhail Al-Salam
  • Ahmed Al Mahrouqee
  • S. Beegam
  • Badreldin H. Ali
Toxicology Investigation


Cisplatin is commonly used against several solid tumors, and oxaliplatin is an effective cytotoxic drug used in colorectal cancer. A major clinical issue affecting 10–40 % of patients treated with cisplatin or oxaliplatin is severe peripheral neuropathy causing sensory, motor, and autonomic dysfunction, with symptoms including cold sensitivity and neuropathic pain. The biochemical basis of the neurotoxicity is uncertain, but is associated with oxidative stress. Curcumin (a natural phenolic yellow pigment) has strong antioxidant, anticancer, and anti-inflammatory actions. Here we report the possible protective effect of curcumin on some cisplatin- and oxaliplatin-induced behavioral, biochemical, and histopathological alterations in rats. Twenty-four hours after the end of treatments some motor and behavioral tests (motor activity, thermal and mechanical nociception, and neuromuscular coordination) were conducted, followed by measuring plasma neurotensin platinum concentration in the sciatic nerve, and studying the histopathology of the sciatic nerve. Oxaliplatin (4 mg/kg) and cisplatin (2 mg/kg) [each given twice weekly, in a total of nine intraperitoneal injections over 4.5 weeks] significantly increased plasma neurotensin concentration, caused specific damage in the histology of the sciatic nerve and produced variable effects in the motor and behavioral tests. Oral curcumin (10 mg/kg, 4 days before the platinum drug, and thereafter, concomitantly with it for 4.5 weeks) reversed the alterations in the plasma neurotensin and sciatic nerve platinum concentrations, and markedly improved sciatic nerve histology in the platinum-treated rats. Larger experiments using a wider dose range of oxaliplatin, cisplatin, and curcumin are required to fully elucidate the possible protective role of curcumin in platinum-induced neurotoxicity.


Cisplatin Oxaliplatin Curcumin Rats Neurotoxicity 



This work was financially supported by a grant from SQU, Oman (IG/MED/MEDE/09/01). The oxaliplatin used was a kind gift from Sanofi-Aventis, Paris, France. Thanks are due to the staff of the SQU Animal House for looking after the rats.


  1. 1.
    Saif MW, Reardon J (2005) Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag 1:249–58PubMedGoogle Scholar
  2. 2.
    Shah N, Dizon DS (2009) New-generation platinum agents for solid tumors. Future Oncol 5:33–42PubMedCrossRefGoogle Scholar
  3. 3.
    Grothey A (2005) Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 5(Suppl 1):S38–46PubMedCrossRefGoogle Scholar
  4. 4.
    Broomand A, Jerremalm E, Yachnin J, Ehrsson H, Elinder F (2009) Oxaliplatin neurotoxicity—no general ion channel surface-charge effect. J Negat Results Biomed 8:2PubMedCrossRefGoogle Scholar
  5. 5.
    Cavaletti G, Marmiroli P (2011) Chemotherapy-induced peripheral neurotoxicity. Nature Review Neurology 6:657–666CrossRefGoogle Scholar
  6. 6.
    Holmes J, Stanko J, Varchenko M, Ding H, Madden VJ, Bagnell CR, Wyrick SD, Chaney SG (1998) Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model. Toxicol Sci 46:342–351PubMedGoogle Scholar
  7. 7.
    Webster RG, Brain KL, Wilson RH, Grem JL, Vincent A (2005) Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels. Br J Pharmacol 146:1027–1039PubMedCrossRefGoogle Scholar
  8. 8.
    Montagnani F, Turrisi G, Marinozzi C, Aliberti C, Fiorentini G (2011) Effectiveness and safety of oxaliplatin compared to cisplatin for advanced, unrespectable gastric cancer: a systematic review and meta-analysis. Gastric Cancer 14:50–55PubMedCrossRefGoogle Scholar
  9. 9.
    Podratz JL, Knight AM, Ta LE, Staff NP, Gass JM, Genelin K, Schlattau A, Lathroum L, Windebank AJ (2011) Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis 41:661–668PubMedCrossRefGoogle Scholar
  10. 10.
    Shord SS, Bernard SA, Lindley C, Blodgett A, Mehta V, Churchel MA, Poole M, Pescatore SL, Luo FR, Chaney SG (2002) Oxaliplatin biotransformation and pharmacokinetics: a pilot study to determine the possible relationship to neurotoxicity. Anticancer Res 22:2301–2309PubMedGoogle Scholar
  11. 11.
    Carozzi VA, Marmiroli P, Cavaletti G (2010) The role of oxidative stress and anti-oxidant treatment in platinum-induced peripheral neurotoxicity. Curr Cancer Drug Targets 10:670–682PubMedCrossRefGoogle Scholar
  12. 12.
    Mendonça LM, Dos Santos GC, Antonucci GA, Dos Santos AC, Bianchi ML, Antunes LM (2009) Evaluation of the cytotoxicity and genotoxicity of curcumin in PC12 cells. Mutat Res 675:29–34PubMedCrossRefGoogle Scholar
  13. 13.
    Albers JW, Chaudhry V, Cavaletti G, Donehower RC (2011) Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev 16:2, CD005228Google Scholar
  14. 14.
    Ali BH (2010) Amelioration of oxaliplatin neurotoxicity by drugs in humans and experimental animals: a minireview of recent literature. Basic Clin Pharmacol Toxicol 106:272–279PubMedGoogle Scholar
  15. 15.
    Durand JP, Deplanque G, Montheil V, Gornet JM, Scotte F, Mir O, Cessot A, Coriat R, Raymond E, Mitry E, Herait P, Yataghene Y, Goldwasser F (2011) Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol 23:200–205PubMedCrossRefGoogle Scholar
  16. 16.
    Ali BH, Marrif H, Noureldyem SA, Bakhiet AO, Blunden G (2006) Some biological properties of curcumin. A review. Natural Product Communications 1:509–521Google Scholar
  17. 17.
    Jurenka JS (2009) Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 14:141–153PubMedGoogle Scholar
  18. 18.
    Shanmugam MK, Kannaiyan R, Sethi G (2011) Targeting cell signaling and apoptotic pathways by dietary agents: role in the prevention and treatment of cancer. Nutr Cancer 63:161–173PubMedCrossRefGoogle Scholar
  19. 19.
    Shehzad A, Ha T, Subhan F, Lee YS (2011) New mechanisms and the anti-inflammatory role of curcumin in obesity and obesity-related metabolic diseases. Eur J Nutr 50:151–161PubMedCrossRefGoogle Scholar
  20. 20.
    Weissenberger J, Priester M, Bernreuther C, Rakel S, Glatzel M, Seifert V, Kögel D (2010) Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin Cancer Res 16:5781–5795PubMedCrossRefGoogle Scholar
  21. 21.
    Lapchak PA (2011) Neuroprotective and neurotrophic curcuminoids to treat stroke: a translational perspective. Expert Opin Investig Drugs 20:13–22PubMedCrossRefGoogle Scholar
  22. 22.
    Ataie A, Sabetkasaei M, Haghparast A, Moghaddam AH, Kazeminejad B (2010) Neuroprotective effects of the polyphenolic antioxidant agent, curcumin, against homocysteine-induced cognitive impairment and oxidative stress in the rat. Pharmacol Biochem Behav 96:378–385PubMedCrossRefGoogle Scholar
  23. 23.
    Guillemette A, Dansereau MA, Beaudet N, Richelson E, Sarret P. Intrathecal administration of NTS1 agonists reverses nociceptive behaviors in a rat model of neuropathic pain. Eur J Pain. 2012. In press.Google Scholar
  24. 24.
    Cavaletti G, Tredici G, Petruccioli MG, Dondè E, Tredici P, Marmiroli P, Minoia C, Ronchi A, Bayssas M, Etienne GG (2001) Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer 37:2457–2463PubMedCrossRefGoogle Scholar
  25. 25.
    Ali BH, Ziada A, Al Husseni I, Beegam S, Nemmar A (2011) Motor and behavioral changes in rats with adenine-induced chronic renal failure: influence of acacia gum treatment. Exp Biol Med (Maywood) 236:107–112CrossRefGoogle Scholar
  26. 26.
    Pizziketti RJ, Pressman NS, Geller EB, Cowan A, Adler MW (1985) Rat cold water tail-flick: a novel analgesic test that distinguishes opioid agonists from mixed agonist-antagonists. Eur J Pharmacol 119:23–29PubMedCrossRefGoogle Scholar
  27. 27.
    Ali BH, Al-Moundhri M, Tageldin M, Al Husseini IS, Mansour MA, Nemmar A, Tanira MO (2008) Ontogenic aspects of cisplatin-induced nephrotoxicity in rats. Food Chem Toxicol 46:3355–3359PubMedCrossRefGoogle Scholar
  28. 28.
    Cavaletti G, Tredici G, Marmiroli P, Petruccioli MG, Barajon I, Fabbrica D (1992) Morphometric study of the sensory neuron and peripheral nerve changes induced by chronic cisplatin (DDP) administration in rats. Acta Neuropathol 84:364–71PubMedGoogle Scholar
  29. 29.
    Wongtawatchai T, Agthong S, Kaewsema A, Chentanez V (2009) Sex-related differences in cisplatin-induced neuropathy in rats. J Med Assoc Thai 92:1485–1491PubMedGoogle Scholar
  30. 30.
    Howells LM, Sale S, Sriramareddy SN, Irving GR, Jones DJ, Ottley CJ, Pearson DG, Mann CD, Manson MM, Berry DP, Gescher A, Steward WP, Brown K (2011) Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. Int J Cancer 129:476–486PubMedCrossRefGoogle Scholar
  31. 31.
    Cavaletti G, Alberti P, Frigeni B, Piatti M, Susani E (2011) Chemotherapy-induced neuropathy. Curr Treat Options Neurol 13:180–190PubMedCrossRefGoogle Scholar
  32. 32.
    Aggarwal BB, Harikumar KB (2009) Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 41:40–59PubMedCrossRefGoogle Scholar
  33. 33.
    Ali BH, Al-Wabel N, Mahmoud OM, Mousa HM, Hashad M (2005) Curcumin has a palliative action on gentamicin-induced nephrotoxicity in rats. Fundamental Clin Pharmacol 19:473–477CrossRefGoogle Scholar
  34. 34.
    Waly M, Al-Moundhari M, Ali BH (2011) The effect of curcumin on cisplatin and oxaliplatin-induced oxidative stress in human embryonic kidneys (HEK) 293 cells. Renal Failure 33:518–523PubMedCrossRefGoogle Scholar
  35. 35.
    Canta A, Chiorazzi A, Carozzi V, Meregalli C, Oggioni N, Sala B, Crippa L, Avezza F, Forestieri D, Rotella G, Zucchetti M, Cavaletti G (2011) In vivo comparative study of the cytotoxicity of a liposomal formulation of cisplatin (lipoplatin™). Cancer Chemother Pharmacol 68:1001–1008PubMedCrossRefGoogle Scholar
  36. 36.
    Kumar P, Padi SS, Naidu PS, Kumar A (2007) Possible neuroprotective mechanisms of curcumin in attenuating 3-nitropropionic acid-induced neurotoxicity. Methods Find Exp Clin Pharmacol 29:19–25PubMedCrossRefGoogle Scholar
  37. 37.
    Mustain WC, Rychahou PG, Evers BM (2011) The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes 18:75–82PubMedCrossRefGoogle Scholar
  38. 38.
    Wachi M, Fujimaki M, Nakamura H, Inazuki G (1996) Effects of ethanol administration on brain neurotensin-like immunoreactivity in rats. Acta Neurol Scand 93:211–214PubMedCrossRefGoogle Scholar
  39. 39.
    Antunes LM, Darin JD, Bianchi NL (2001) Effects of the antioxidants curcumin or selenium on cisplatin-induced nephrotoxicity and lipid peroxidation in rats. Pharmacol Res 43:145–150PubMedCrossRefGoogle Scholar

Copyright information

© American College of Medical Toxicology 2012

Authors and Affiliations

  • Mansour S. Al Moundhri
    • 1
  • Suhail Al-Salam
    • 2
  • Ahmed Al Mahrouqee
    • 3
  • S. Beegam
    • 3
  • Badreldin H. Ali
    • 3
  1. 1.Department of Medicine, College of Medicine and Health SciencesSultan Qaboos UniversityAl-KhodSultanate of Oman
  2. 2.Department of Pathology, Faculty of MedicineUAE UniversityAl AinUnited Arab Emirates
  3. 3.Pharmacology and Clinical Pharmacy, College of Medicine and Health SciencesSultan Qaboos UniversityAl KhodOman

Personalised recommendations