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Targeting Axon Integrity to Prevent Chemotherapy-Induced Peripheral Neuropathy

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is an irreversible off-target adverse effect of many chemotherapeutic agents such as paclitaxel, yet its mechanism is poorly understood and no preventative measure is available. CIPN is characterized by peripheral nerve damages resulting in permanent sensory function deficits. Our recent unbiased genome-wide analysis revealed that heat shock protein (Hsp) 27 is part of a transcriptional network induced by axonal injury and highly enriched for genes involved in adaptive neuronal responses, particularly axonal regeneration. To examine if Hsp27 could prevent the occurrence of CIPN, we first demonstrated that paclitaxel-induced allodynia was associated directly with axonal degeneration in sensory neurons in a mouse model of CIPN. We therefore hypothesize that by preventing axonal degeneration could prevent the development of CIPN. We drove expression of human Hsp27 (hHsp27) specifically in neurons. Development of mechanical and thermal allodynia was prevented completely in paclitaxel-treated hHsp27 transgenic mice. Strikingly, hHsp27 protected against paclitaxel-induced neurotoxicity in vivo including degeneration of afferent nerve fibers, demyelination, mitochondrial swelling, apoptosis, and restored sensory nerve action potential. Finally, we delineated signaling cascades that link CIPN development to caspase 3 and RhoA/cofilin activation in sensory neurons and peripheral nerves. hHsp27 exerted anti-apoptotic effect and maintained axon integrity by restoring caspase 3 and RhoA expression to basal levels. Taken together, our data suggest that by preventing axonal degeneration might prove beneficial as anti-CIPN drugs, which represents an emerging research area for therapeutic development.

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References

  1. Au NP, Fang Y, Xi N, Lai KW, Ma CH (2014) Probing for chemotherapy-induced peripheral neuropathy in live dorsal root ganglion neurons with atomic force microscopy. Nanomedicine 10(6):1323–1333

    CAS  PubMed  Google Scholar 

  2. Jaggi AS, Singh N (2011) Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology 291(1–3):1–9

    CAS  PubMed  Google Scholar 

  3. Pachman DR, Barton DL, Watson JC, Loprinzi CL (2011) Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther 90(3):377–387

    CAS  PubMed  Google Scholar 

  4. Dougherty PM, Cata JP, Cordella JV, Burton A, Weng HR (2004) Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients. Pain 109(1–2):132–142

    CAS  PubMed  Google Scholar 

  5. Windebank AJ, Grisold W (2008) Chemotherapy-induced neuropathy. J Peripher Nerv Syst 13(1):27–46

    CAS  PubMed  Google Scholar 

  6. Verstappen CC, Koeppen S, Heimans JJ, Huijgens PC, Scheulen ME, Strumberg D, Kiburg B, Postma TJ (2005) Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening. Neurology 64(6):1076–1077

    CAS  PubMed  Google Scholar 

  7. Rowinsky EK, Chaudhry V, Cornblath DR, Donehower RC (1993) Neurotoxicity of Taxol. J Natl Cancer Inst Monogr 15:107–115

    Google Scholar 

  8. Michaud LB, Valero V, Hortobagyi G (2000) Risks and benefits of taxanes in breast and ovarian cancer. Drug Saf 23(5):401–428

    CAS  PubMed  Google Scholar 

  9. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4):253–265

    CAS  PubMed  Google Scholar 

  10. Lee JJ, Swain SM (2006) Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol 24(10):1633–1642

    CAS  PubMed  Google Scholar 

  11. Hilkens PH, ven den Bent MJ (1997) Chemotherapy-induced peripheral neuropathy. J Peripher Nerv Syst 2(4):350–361

    CAS  PubMed  Google Scholar 

  12. Siau C, Xiao W, Bennett GJ (2006) Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Exp Neurol 201(2):507–514

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang MS, Davis AA, Culver DG, Wang Q, Powers JC, Glass JD (2004) Calpain inhibition protects against Taxol-induced sensory neuropathy. Brain 127(Pt 3):671–679

    PubMed  Google Scholar 

  14. Callizot N, Andriambeloson E, Glass J, Revel M, Ferro P, Cirillo R, Vitte PA, Dreano M (2008) Interleukin-6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activity. Cancer Chemother Pharmacol 62(6):995–1007

    CAS  PubMed  Google Scholar 

  15. Smith SB, Crager SE, Mogil JS (2004) Paclitaxel-induced neuropathic hypersensitivity in mice: responses in 10 inbred mouse strains. Life Sci 74(21):2593–2604

    CAS  PubMed  Google Scholar 

  16. Boyette-Davis J, Dougherty PM (2011) Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline. Exp Neurol 229(2):353–357

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Boyette-Davis J, Xin W, Zhang H, Dougherty PM (2011) Intraepidermal nerve fiber loss corresponds to the development of taxol-induced hyperalgesia and can be prevented by treatment with minocycline. Pain 152(2):308–313

    CAS  PubMed  Google Scholar 

  18. Tatsushima Y, Egashira N, Kawashiri T, Mihara Y, Yano T, Mishima K, Oishi R (2011) Involvement of substance P in peripheral neuropathy induced by paclitaxel but not oxaliplatin. J Pharmacol Exp Ther 337(1):226–235

    CAS  PubMed  Google Scholar 

  19. Pan YA, Misgeld T, Lichtman JW, Sanes JR (2003) Effects of neurotoxic and neuroprotective agents on peripheral nerve regeneration assayed by time-lapse imaging in vivo. J Neurosci 23(36):11479–11488

    CAS  PubMed  Google Scholar 

  20. Vuorinen VS, Roytta M (1990) Taxol-induced neuropathy after nerve crush: long-term effects on regenerating axons. Acta Neuropathol 79(6):663–671

    CAS  PubMed  Google Scholar 

  21. Ma CH, Omura T, Cobos EJ, Latremoliere A, Ghasemlou N, Brenner GJ, van Veen E, Barrett L et al (2011) Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice. J Clin Invest 121(11):4332–4347

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lavoie JN, Gingras-Breton G, Tanguay RM, Landry J (1993) Induction of Chinese hamster HSP27 gene expression in mouse cells confers resistance to heat shock. HSP27 stabilization of the microfilament organization. J Biol Chem 268(5):3420–3429

    CAS  PubMed  Google Scholar 

  23. Stetler RA, Cao G, Gao Y, Zhang F, Wang S, Weng Z, Vosler P, Zhang L et al (2008) Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. J Neurosci 28(49):13038–13055

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Huot J, Houle F, Spitz DR, Landry J (1996) HSP27 phosphorylation-mediated resistance against actin fragmentation and cell death induced by oxidative stress. Cancer Res 56(2):273–279

    CAS  PubMed  Google Scholar 

  25. Lavoie JN, Lambert H, Hickey E, Weber LA, Landry J (1995) Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27. Mol Cell Biol 15(1):505–516

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Pichon S, Bryckaert M, Berrou E (2004) Control of actin dynamics by p38 MAP kinase - Hsp27 distribution in the lamellipodium of smooth muscle cells. J Cell Sci 117(Pt 12):2569–2577

    CAS  PubMed  Google Scholar 

  27. Benndorf R, Hayess K, Ryazantsev S, Wieske M, Behlke J, Lutsch G (1994) Phosphorylation and supramolecular organization of murine small heat shock protein HSP25 abolish its actin polymerization-inhibiting activity. J Biol Chem 269(32):20780–20784

    CAS  PubMed  Google Scholar 

  28. Chaudhuri S, Smith PG (2008) Cyclic strain-induced HSP27 phosphorylation modulates actin filaments in airway smooth muscle cells. Am J Respir Cell Mol Biol 39(3):270–278

    CAS  PubMed  Google Scholar 

  29. Tezel G, Wax MB (2000) The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells. J Neurosci 20(10):3552–3562

    CAS  PubMed  Google Scholar 

  30. Caroni P (1997) Overexpression of growth-associated proteins in the neurons of adult transgenic mice. J Neurosci Methods 71(1):3–9

    CAS  PubMed  Google Scholar 

  31. Torres L, Danver J, Ji K, Miyauchi JT, Chen D, Anderson ME, West BL, Robinson JK et al (2016) Dynamic microglial modulation of spatial learning and social behavior. Brain Behav Immun 55:6–16

    PubMed  Google Scholar 

  32. Flatters SJ, Bennett GJ (2004) Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109(1–2):150–161

    CAS  PubMed  Google Scholar 

  33. Polomano RC, Mannes AJ, Clark US, Bennett GJ (2001) A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain 94(3):293–304

    CAS  PubMed  Google Scholar 

  34. Griffin RS, Costigan M, Brenner GJ, Ma CH, Scholz J, Moss A, Allchorne AJ, Stahl GL et al (2007) Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J Neurosci 27(32):8699–8708

    CAS  PubMed  Google Scholar 

  35. Korngut L, Ma CH, Martinez JA, Toth CC, Guo GF, Singh V, Woolf CJ, Zochodne DW (2012) Overexpression of human HSP27 protects sensory neurons from diabetes. Neurobiol Dis 47(3):436–443

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Dixon WJ (1965) The up-and-down method for small samples. J Am Stat Assoc 60(312):967–978

    Google Scholar 

  37. Ward SJ, Ramirez MD, Neelakantan H, Walker EA (2011) Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice. Anesth Analg 113(4):947–950

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Choi Y, Yoon YW, Na HS, Kim SH, Chung JM (1994) Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59(3):369–376

    CAS  PubMed  Google Scholar 

  39. Materazzi S, Fusi C, Benemei S, Pedretti P, Patacchini R, Nilius B, Prenen J, Creminon C et al (2012) TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Arch 463(4):561–569

    CAS  PubMed  Google Scholar 

  40. Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87(2):149–158

    CAS  PubMed  Google Scholar 

  41. Asthana P, Zhang N, Kumar G, Chine VB, Singh KK, Mak YL, Chan LL, Lam PKS et al (2018) Pacific ciguatoxin induces excitotoxicity and neurodegeneration in the motor cortex via caspase 3 activation: implication for irreversible motor deficit. Mol Neurobiol 55(8):6769–6787

    CAS  PubMed  Google Scholar 

  42. Painter MW, Brosius Lutz A, Cheng YC, Latremoliere A, Duong K, Miller CM, Posada S, Cobos EJ et al (2014) Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration. Neuron 83(2):331–343

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bobylev I, Joshi AR, Barham M, Ritter C, Neiss WF, Höke A, Lehmann HC (2015) Paclitaxel inhibits mRNA transport in axons. Neurobiol Dis 82:321–331

    CAS  PubMed  Google Scholar 

  44. Wozniak KM, Wu Y, Farah MH, Littlefield BA, Nomoto K, Slusher BS (2013) Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy. Neurotox Res 24(3):338–344

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ma KH, Hung HA, Srinivasan R, Xie H, Orkin SH, Svaren J (2015) Regulation of peripheral nerve myelin maintenance by gene repression through polycomb repressive complex 2. J Neurosci 35(22):8640–8652

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Boehmerle W, Huehnchen P, Peruzzaro S, Balkaya M, Endres M (2014) Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice. Sci Rep 4:6370

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Cliffer KD, Siuciak JA, Carson SR, Radley HE, Park JS, Lewis DR, Zlotchenko E, Nguyen T et al (1998) Physiological characterization of Taxol-induced large-fiber sensory neuropathy in the rat. Ann Neurol 43(1):46–55

    CAS  PubMed  Google Scholar 

  48. Huehnchen P, Boehmerle W, Endres M (2013) Assessment of paclitaxel induced sensory polyneuropathy with “Catwalk” automated gait analysis in mice. PLoS One 8(10):e76772

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Quasthoff S, Hartung HP (2002) Chemotherapy-induced peripheral neuropathy. J Neurol 249(1):9–17

    CAS  PubMed  Google Scholar 

  50. Sahenk Z, Barohn R, New P, Mendell JR (1994) Taxol neuropathy: electrodiagnostic and sural nerve biopsy findings. Arch Neurol 51(7):726–729

    CAS  PubMed  Google Scholar 

  51. van den Bent MJ, van Raaij-van den Aarssen VJ, Verweij J, Doorn PA, Sillevis Smitt PA (1997) Progression of paclitaxel-induced neuropathy following discontinuation of treatment. Muscle Nerve 20(6):750–752

    PubMed  Google Scholar 

  52. Flatters SJ, Bennett GJ (2006) Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 122(3):245–257

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Arrieta O, Hernandez-Pedro N, Fernández-González-Aragón M, Saavedra-Perez D, Campos-Parra A, Rios-Trejo M, Cerón-Lizárraga T, Martínez-Barrera L et al (2011) Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer. Neurology 77(10):987–995

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Lipton RB, Apfel SC, Dutcher JP, Rosenberg R, Kaplan J, Berger A, Einzig AI, Wiernik P et al (1989) Taxol produces a predominantly sensory neuropathy. Neurology 39(3):368–373

    CAS  PubMed  Google Scholar 

  55. Chen X, Stubblefield MD, Custodio CM, Hudis CA, Seidman AD, DeAngelis LM (2013) Electrophysiological features of taxane-induced polyneuropathy in patients with breast cancer. J Clin Neurophysiol 30(2):199–203

    PubMed  Google Scholar 

  56. Park SB, Lin CSY, Krishnan AV, Friedlander ML, Lewis CR, Kiernan MC (2011) Early, progressive, and sustained dysfunction of sensory axons underlies paclitaxel-induced neuropathy. Muscle Nerve 43(3):367–374

    PubMed  Google Scholar 

  57. Weil MT, Mobius W, Winkler A, Ruhwedel T, Wrzos C, Romanelli E, Bennett JL, Enz L et al (2016) Loss of myelin basic protein function triggers myelin breakdown in models of demyelinating diseases. Cell Rep 16(2):314–322

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Purves D, Augustine G, Fitzpatrick D, Katz L, LaMantia A, McNamara J, Williams S (2004) Increased conduction velocity as a result of myelination. Neuroscience. In: Neuroscience, 3nd edn. Sinauer Associates, Sunderland, pp 63–65

  59. Flatters SJ, Xiao W-H, Bennett GJ (2006) Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy. Neurosci Lett 397(3):219–223

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Xiao WH, Bennett GJ (2012) Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin. Pain 153(3):704–709

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Griffiths LA, Flatters SJ (2015) Pharmacological modulation of the mitochondrial electron transport chain in paclitaxel-induced painful peripheral neuropathy. J Pain 16(10):981–994

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Krukowski K, Nijboer CH, Huo X, Kavelaars A, Heijnen CJ (2015) Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor pifithrin-μ. Pain 156(11):2184–2192

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Joseph EK, Levine JD (2006) Mitochondrial electron transport in models of neuropathic and inflammatory pain. Pain 121(1):105–114

    CAS  PubMed  Google Scholar 

  64. Zheng H, Xiao WH, Bennett GJ (2012) Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol 238(2):225–234

    CAS  PubMed  Google Scholar 

  65. Neumar RW, Xu YA, Gada H, Guttmann RP, Siman R (2003) Cross-talk between calpain and caspase proteolytic systems during neuronal apoptosis. J Biol Chem 278(16):14162–14167

    CAS  PubMed  Google Scholar 

  66. Huang ZZ, Li D, Liu CC, Cui Y, Zhu HQ, Zhang WW, Li YY, Xin WJ (2014) CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. Brain Behav Immun 40:155–165

    CAS  PubMed  Google Scholar 

  67. Friesland A, Weng Z, Duenas M, Massa SM, Longo FM, Lu Q (2014) Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR. Neurotoxicology 45:81–90

    CAS  PubMed  Google Scholar 

  68. James SE, Burden H, Burgess R, Xie Y, Yang T, Massa SM, Longo FM, Lu Q (2008) Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology 29(4):605–612

    CAS  PubMed  PubMed Central  Google Scholar 

  69. James SE, Dunham M, Carrion-Jones M, Murashov A, Lu Q (2010) Rho kinase inhibitor Y-27632 facilitates recovery from experimental peripheral neuropathy induced by anti-cancer drug cisplatin. Neurotoxicology 31(2):188–194

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Qiu Y, Chen WY, Wang ZY, Liu F, Wei M, Ma C, Huang YG (2016) Simvastatin attenuates neuropathic pain by inhibiting the RhoA/LIMK/cofilin pathway. Neurochem Res 41(9):2457–2469

    CAS  PubMed  Google Scholar 

  71. Scuteri A, Nicolini G, Miloso M, Bossi M, Cavaletti G, Windebank AJ, Tredici G (2006) Paclitaxel toxicity in post-mitotic dorsal root ganglion (DRG) cells. Anticancer Res 26(2A):1065–1070

    CAS  PubMed  Google Scholar 

  72. Melli G, Taiana M, Camozzi F, Triolo D, Podini P, Quattrini A, Taroni F, Lauria G (2008) Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol 214(2):276–284

    CAS  PubMed  Google Scholar 

  73. Liu XJ, Zhang Y, Liu T, Xu ZZ, Park CK, Berta T, Jiang D, Ji RR (2014) Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Res 24(11):1374–1377

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Berta T, Park CK, Xu ZZ, Xie RG, Liu T, Lu N, Liu YC, Ji RR (2014) Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-alpha secretion. J Clin Invest 124(3):1173–1186

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Berta T, Qadri YJ, Chen G, Ji RR (2016) Microglial signaling in chronic pain with a special focus on caspase 6, p38 MAP kinase, and sex dependence. J Dent Res 95(10):1124–1131

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Benn SC, Perrelet D, Kato AC, Scholz J, Decosterd I, Mannion RJ, Bakowska JC, Woolf CJ (2002) Hsp27 upregulation and phosphorylation is required for injured sensory and motor neuron survival. Neuron 36(1):45–56

    CAS  PubMed  Google Scholar 

  77. André N, Braguer D, Brasseur G, Gonçalves A, Lemesle-Meunier D, Guise S, Jordan MA, Briand C (2000) Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells. Cancer Res 60(19):5349–5353

    PubMed  Google Scholar 

  78. Mehlen P, Kretz-Remy C, Preville X, Arrigo A-P (1996) Human hsp27, Drosophila hsp27 and human alphaB-crystallin expression-mediated increase in glutathione is essential for the protective activity of these proteins against TNFalpha-induced cell death. EMBO J 15(11):2695–2706

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang C, Song S, Zhang Y, Ge Y, Fang X, Huang T, Du J, Gao J (2015) Inhibition of the Rho/Rho kinase pathway prevents lipopolysaccharide-induced hyperalgesia and the release of TNF-alpha and IL-1beta in the mouse spinal cord. Sci Rep 5:14553

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Zulauf L, Coste O, Marian C, Moser C, Brenneis C, Niederberger E (2009) Cofilin phosphorylation is involved in nitric oxide/cGMP-mediated nociception. Biochem Biophys Res Commun 390(4):1408–1413

    CAS  PubMed  Google Scholar 

  81. Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR (2005) Local translation of RhoA regulates growth cone collapse. Nature 436(7053):1020–1024

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Qin Q, Baudry M, Liao G, Noniyev A, Galeano J, Bi X (2009) A novel function for p53: regulation of growth cone motility through interaction with Rho kinase. J Neurosci 29(16):5183–5192

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Tanaka H, Yamashita T, Asada M, Mizutani S, Yoshikawa H, Tohyama M (2002) Cytoplasmic p21(Cip1/WAF1) regulates neurite remodeling by inhibiting Rho-kinase activity. J Cell Biol 158(2):321–329

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sun X, Zhou Z, Fink DJ, Mata M (2013) HspB1 silences translation of PDZ-RhoGEF by enhancing miR-20a and miR-128 expression to promote neurite extension. Mol Cell Neurosci 57:111–119

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Chandran V, Coppola G, Nawabi H, Omura T, Versano R, Huebner EA, Zhang A, Costigan M et al (2016) A systems-level analysis of the peripheral nerve intrinsic axonal growth program. Neuron 89(5):956–970

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is supported in part by GRF grants from The Research Grant Council of the Hong Kong Special Administrative Region Government (CityU 11100015 and CityU 11100417), and the Health and Medical Research Fund, Food and Health Bureau, Hong Kong Special Administrative Region Government (05160126) award to Chi Ma.

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  1. Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, Hong Kong

    Virendra Bhagawan Chine, Ngan Pan Bennett Au, Gajendra Kumar & Chi Him Eddie Ma

  2. Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, Hong Kong

    Chi Him Eddie Ma

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  1. Virendra Bhagawan Chine
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Contributions

VC carried out the neurobehavioral assessment, in vivo electrophysiological recording, immunohistochemistry of skin and nerve biopsies, electron microscopy, TUNEL assay, and Western blot analysis for cleaved caspase 3 protein expression. NPBA performed in vitro DRG culture analysis and Western blot analysis for RhoA/cofilin activation. GK validated and standardized SNAP and NCV recording. CHEM conceived the project, designed the study, and wrote the manuscript with inputs from all authors. All authors read and approved the final manuscript.

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Correspondence to Chi Him Eddie Ma.

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Chine, V.B., Au, N.P.B., Kumar, G. et al. Targeting Axon Integrity to Prevent Chemotherapy-Induced Peripheral Neuropathy. Mol Neurobiol 56, 3244–3259 (2019). https://doi.org/10.1007/s12035-018-1301-8

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