Altered phosphorylation of mitogen-activated protein kinases in dorsal root ganglia and sciatic nerve of rats with cisplatin-induced neuropathy

Tulaporn Wongtawatchai 1 , Sithiporn Agthong 1 , Athitaya Kaewsema 1  and Vilai Chentanez 1
  • 1 Peripheral Nerve Research Unit, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand


Background: Peripheral neuropathy is a major side effect of cisplatin. Cisplatin preferentially accumulates in the dorsal root ganglia (DRG) and causes neuronal apoptosis. In vitro studies have implicated mitogenactivated protein kinases (MAPKs) in cisplatin-induced apoptosis. However, this has not been confirmed in vivo.

Objective: We studied the phosphorylation of MAPKs, ERK, JNK, and p38, in the DRG and sciatic nerve of rats treated with cisplatin, and correlated it with the neuropathic abnormalities.

Methods: Cisplatin 2 mg/kg was intraperitoneally injected in rats twice a week for five consecutive weeks. Neuropathy was assessed by measuring hind-paw thermal and mechanical thresholds, sciatic motor nerve conduction velocity (MNCV) and morphometric evaluation of DRG and sciatic nerve at various time points after the start of cisplatin treatment. Western blot analysis was done to determine the ratio of phosphorylated to total forms of MAPKs in the DRG and sciatic nerve.

Results: Cisplatin induced transient thermal hypoalgesia, late reduction in MNCV and histopathological abnormalities of DRG and sciatic nerve indicating the neuropathy. ERK was activated in the nerve and DRG in the eighth and twelfth weeks, respectively. Transient activation of JNK in the nerve and DRG was observed only in the first week. At the same time point to JNK, p38 was temporarily inhibited in the DRG. Late activation of ERK was correlated with the presence of pathological changes, suggesting the possible role of ERK in these abnormalities. No correlation between MAPKs and functional abnormalities was observed.

Conclusion: MAPK ERK might play a role in cisplatin-induced structural alterations in the DRG and sciatic nerve and can be the therapeutic target. However, to prove this hypothesis, future studies using the ERK inhibitor must be done.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Boulikas T, Vougiouka M. Recent clinical trials using cisplatin, carboplatin and their combination chemotherapy drugs (review). Oncol Rep. 2004; 11: 559-95.

  • 2. Krarup-Hansen A, Fugleholm K, Helweg-Larsen S, Hauge EN, Schmalbruch H, Trojaborg W, et al. Examination of distal involvement in cisplatin induced neuropathy in man. An electrophysiological and histological study with particular reference to touch receptor function. Brain. 1993; 116:1017-41.

  • 3. Krarup-Hansen A, Helweg-Larsen S, Schmalbruch H, Rorth M, Krarup C. Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain. 2007; 130:1076-88.

  • 4. McDonald ES, Randon KR, Knight A, Windebank AJ. Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. Neurobiol Dis. 2005; 18:305-13.

    • Crossref
    • Export Citation
  • 5. Dzagnidze A, Katsarava Z, Makhalova J, Liedert B, Yoon MS, Kaube H, et al. Repair capacity for platinum- DNA adducts determines the severity of cisplatininduced peripheral neuropathy. J Neurosci. 2007; 27: 9451-7.

    • Crossref
    • Export Citation
  • 6. Gill JS, Windebank AJ. Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. J Clin Invest. 1998; 101:2842-50.

  • 7. Fischer SJ, McDonald ES, Gross L, Windebank AJ. Alterations in cell cycle regulation underlie cisplatin induced apoptosis of dorsal root ganglion neurons in vivo. Neurobiol Dis. 2001; 8:1027-35.

    • Crossref
    • Export Citation
  • 8. Leonetti C, Biroccio A, Gabellini C, Scarsella M, Maresca V, Flori E, et al. α-tocopherol protects againt cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer. 2003; 104:243-50.

  • 9. Pace A, Giannarelli D, Gali­ E, Savarese A, Carpano S, Della Giulia M, et al. Vitamin E neuroprotection for cisplatin neuropathy a randomized, placebo-controlled trial. J Neurology. 2010; 74:762-6.

  • 10. Brozovic A, Osmak M. Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatinresistance. Cancer Lett. 2007; 251:1-16.

  • 11. Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol. 2005; 289:F166-74.

  • 12. Scuteri A, Galimberti A, Maggioni D, Ravasi M, Pasini S, Nicolini G, et al. Role of MAPKs in platinum-induced neuronal apoptosis. Neurotoxicology. 2009; 30:312-9.

    • Crossref
    • Export Citation
  • 13. Authier N, Gillet JP, Fialip J, Eschalier A, Coudore F. An animal model of nociceptive peripheral neuropathy following repeated cisplatin injections. Exp Neurol. 2003; 182:12-20.

  • 14. Chentanez V, Cha-oumphol P, Kaewsema A, Agthong S, Huanmanop T. Accuracy of the three-window sampling method in morphometric analysis of human sural nerve. J Neurosci Methods. 2006; 157:154-7.

  • 15. Tredici G, Braga M, Nicolini G, Miloso M, Marmiroli P, Schenone A, et al. Effect of recombinant human nerve growth factor on cisplatin neurotoxicity in rats. Exp Neurol. 1999; 159:551-8.

  • 16. Schenker M, Kraftsik R, Glauser L, Kuntzer T, Bogousslavsky J, Barakat-Walter I. Thyroid hormone reduces the loss of axotomized sensory neurons in dorsal root ganglia after sciatic nerve transection in adult rat. ExpNeurol. 2003; 184:225-36.

  • 17. Wongtawatchai T, Agthong S, Kaewsema A, Chentanez V. Sex-related differences in cisplatininduced neuropathy in rats. J Med Assoc Thai. 2009; 92:1485-91.

  • 18. Bramhall S, Noack N, Wu M, Loewenberg JR. A simple colorimetric method for determination of protein. Anal Biochem. 1969; 31:146-8.

    • Crossref
    • Export Citation
  • 19. Tredici G, Tredici S, Fabbrica D, Minoia C, Cavaletti G. Experimental cisplatin neuronopathy in rats and the effect of retinoic acid administration. J Neurooncol. 1998; 36:31-40.

    • Crossref
    • Export Citation
  • 20. Boyle FM, Wheeler HR, Shenfield GM. Amelioration of experimental cisplatin and paclitaxel neuropathy with glutamate. J Neurooncol. 1999; 41:107-16.

    • Crossref
    • Export Citation
  • 21. Ozturk G, Erdogan E, Anlar O, Kosem M, Taspinar M. Effect of leukemia inhibitory factor in experimental cisplatin neuropathy in mice. Cytokine. 2005; 29:31-41.

  • 22. Hori K, Ozaki N, Suzuki S, Sugiura Y. Upregulations of P2X(3) and ASIC3 involve in hyperalgesia induced by cisplatin administration in rats. Pain. 2010; 149:393-405.

  • 23. Muller LJ, Gerritsen vdH, Moorer-van Delft CM, Gispen WH, Roubos EW. Morphological and electrophysiological study of the effects of cisplatin and ORG.2766 on rat spinal ganglion neurons. Cancer Res. 1990; 50:2437-42.

  • 24. Bardos G, Moricz K, Jaszlits L, Rabloczky G, Tory K, Racz I, et al. BGP-15, a hydroximic acid derivative, protects against cisplatin- or taxol induced peripheral neuropathy in rats. Toxicol Appl Pharmacol. 2003; 190: 9-16.

  • 25. Verdé­ E, Vilches JJ, Rodríguez FJ, Ceballos D, Valero A, Navarro X. Physiological and immunohistochemical characterization of cisplatin-induced neuropathy in mice. Muscle Nerve. 1999; 22:329-40.

    • Crossref
    • Export Citation
  • 26. Schmidt Y, Unger JW, Bartke I, Reiter R. Effect of nerve growth factor on peptide neurons in dorsal root ganglia after taxol or cisplatin treatment and in diabetic (db/ db) mice. Exp Neurol. 1995; 132:16-23.

  • 27. Cavaletti G, Tredici G, Marmiroli P, Petruccioli MG, Barajon I, Fabbrica D. Morphometric study of the sensory neuron and peripheral nerve changes induced by chronic cisplatin (DDP) administration in rats. Acta Neuropathol. 1992; 84:364-71.

  • 28. Barajon I, Bersani M, Quartu M, Del Fiacco M, Cavaletti G, Holst JJ, et al. Neuropeptides and morphological changes in cisplatin-induced dorsal root ganglion neuronopathy. Exp Neurol. 1996; 138:93-104.

  • 29. Jirsova K, Mandys V, Gispen WH, Bar PR. Cisplatininduced apoptosis in cultures of human Schwann cells. Neurosci Lett. 2006; 392:22-6.

  • 30. Tanner KD, Levine JD, Topp KS. Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat. J Comp Neurol. 1998; 395:481-92.

  • 31. Lehning EJ, Persaud A, Dyer KR, Jortner BS, LoPachin RM. Biochemical and morphologic characterization of acrylamide peripheral neuropathy. Toxicol Appl Pharmacol. 1998; 151:211-21.

  • 32. Lehning EJ, Jortner BS, Fox JH, Arezzo JC, Kitano T, LoPachin RM. gamma-diketone peripheral neuropathy. I. Quality morphometric analyses of axonal atrophy and swelling. Toxicol Appl Pharmacol. 2000; 165: 127-40.

  • 33. Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, et al. Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci. 2004; 24:10211-22.

    • Crossref
    • Export Citation
  • 34. Kawasaki H, Morooka T, Shimohama S, Kimura J, Hirano T, Gotoh Y, et al. Activation and involvement of p38 mitogen-activated protein kinase in glutamateinduced apoptosis in rat cerebellar granule cells. J Biol Chem. 1997; 272:18518-21.

  • 35. Satoh T, Nakatsuka D, Watanabe Y, Nagata I, Kikuchi H, Namura S. Neuroprotection by MAPK/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons. Neurosci Lett. 2000; 288:163-6.

  • 36. Harding TC, Xue L, Bienemann A, Haywood D, Dickens M, Tolkovsky AM, et al. Inhibition of JNK by overexpression of the JNL binding domain of JIP-1 prevents apoptosis in sympathetic neurons. J Biol Chem. 2001; 276:4531-4.

  • 37. Junn E, Mouradian MM. Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases. J Neurochem. 2001; 78: 374-83.

  • 38. Cavaletti G, Miloso M, Nicolini G, Scuteri A, Tredici G. Emerging role of mitogen-activated protein kinases in peripheral neuropathies. J Peripher Nerv Syst. 2007; 12:175-94.

    • Crossref
    • Export Citation
  • 39. Gozdz A, Habas A, Jaworski J, Zielinska M, Albrecht J, Chlystun M, et al. Role of N-methyl-D-aspartate receptors in the neuroprotective activation of extracellular signal-regulated kinase 1/2 by cisplatin. J Biol Chem. 2003; 278:43663-71.

  • 40. Averill S, Delcroix JD, Michael GJ, Tomlinson DR, Fernyhough P, Priestley JV. Nerve growth factor modulates the activation status and fast axonal transport of ERK 1/2 in adult nociceptive neurones. Mol Cell Neurosci. 2001; 18:183-96.

    • Crossref
    • Export Citation

Journal + Issues