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Antioxidants Attenuate Acute and Chronic Itch: Peripheral and Central Mechanisms of Oxidative Stress in Pruritus

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Abstract

Itch (pruritus) is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the effects of antioxidants in mouse models of acute and chronic itch and explored the potential mechanisms. The effects of systemic administration of the antioxidants N-acetyl-L-cysteine (NAC) and N-tert-butyl-α-phenylnitrone (PBN) were determined by behavioral tests in mouse models of acute itch induced by compound 48/80 or chloroquine, and chronic itch by treatment with a mixture of acetone-diethyl-ether-water. We found that systemic administration of NAC or PBN significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner, attenuated dry skin-induced chronic itch, and suppressed oxidative stress in the affected skin. Antioxidants significantly decreased the accumulation of intracellular reactive oxygen species directly induced by compound 48/80 and chloroquine in the cultured dorsal root ganglia-derived cell line ND7-23. Finally, the antioxidants remarkably inhibited the compound 48/80-induced phosphorylation of extracellular signal-regulated kinase in the spinal cord. These results indicated that oxidative stress plays a critical role in acute and chronic itch in the periphery and spinal cord and antioxidant treatment may be a promising strategy for anti-itch therapy.

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References

  1. Patel KN, Dong X. An itch to be scratched. Neuron 2010, 68: 334–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci 2006, 7: 535–547.

    Article  CAS  PubMed  Google Scholar 

  3. Paus R, Schmelz M, Biro T, Steinhoff M. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest 2006, 116: 1174–1186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Green D, Dong X. The cell biology of acute itch. J Cell Biol 2016, 213: 155–161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med 2013, 368: 1625–1634.

    Article  CAS  PubMed  Google Scholar 

  6. Weidinger S, Novak N. Atopic dermatitis. Lancet 2016, 387: 1109–1122.

    Article  PubMed  Google Scholar 

  7. Chuquilin M, Alghalith Y, Fernandez KH. Neurocutaneous disease: Cutaneous neuroanatomy and mechanisms of itch and pain. J Am Acad Dermatol 2016, 74: 197–212.

    Article  PubMed  Google Scholar 

  8. Szepietowski JC, Reich A. Pruritus in psoriasis: An update. Eur J Pain 2016, 20: 41–46.

    Article  CAS  PubMed  Google Scholar 

  9. Tarikci N, Kocaturk E, Gungor S, Topal IO, Can PU, Singer R. Pruritus in systemic diseases: A review of etiological factors and new treatment modalities. Sci World J 2015, 2015: 803752.

    Article  Google Scholar 

  10. Combs SA, Teixeira JP, Germain MJ. Pruritus in kidney disease. Semin Nephrol 2015, 35: 383–391.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bolier AR, Peri S, Oude Elferink RP, Beuers U. The challenge of cholestatic pruritus. Acta Gastroenterol Belg 2012, 75: 399–404.

    CAS  PubMed  Google Scholar 

  12. Neilly JB, Martin A, Simpson N, MacCuish AC. Pruritus in diabetes mellitus: investigation of prevalence and correlation with diabetes control. Diabetes Care 1986, 9: 273–275.

    Article  CAS  PubMed  Google Scholar 

  13. Yamaoka H, Sasaki H, Yamasaki H, Ogawa K, Ohta T, Furuta H, et al. Truncal pruritus of unknown origin may be a symptom of diabetic polyneuropathy. Diabetes Care 2010, 33: 150–155.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ, Jr. Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat Neurosci 2009, 12: 544–546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Valdes-Rodriguez R, Stull C, Yosipovitch G. Chronic pruritus in the elderly: pathophysiology, diagnosis and management. Drugs Aging 2015, 32: 201–215.

    Article  CAS  PubMed  Google Scholar 

  16. Shim WS, Oh U. Histamine-induced itch and its relationship with pain. Mol Pain 2008, 4: 29.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kim BM, Lee SH, Shim WS, Oh U. Histamine-induced Ca(2+) influx via the PLA(2)/lipoxygenase/TRPV1 pathway in rat sensory neurons. Neurosci Lett 2004, 361: 159–162.

    Article  CAS  PubMed  Google Scholar 

  18. Han L, Dong X. Itch mechanisms and circuits. Annu Rev Biophys 2014, 43: 331–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu Q, Sikand P, Ma C, Tang Z, Han L, Li Z, et al. Mechanisms of itch evoked by beta-alanine. J Neurosci 2012, 32: 14532–14537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 2009, 139: 1353–1365.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wang XL, Tian B, Huang Y, Peng XY, Chen LH, Li JC, et al. Hydrogen sulfide-induced itch requires activation of Cav3.2 T-type calcium channel in mice. Sci Rep 2015, 5: 16768.

  22. Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci 2010, 13: 1460–1462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu T, Ji RR. Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci Bull 2012, 28: 145–154.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000, 408: 239–247.

    Article  CAS  PubMed  Google Scholar 

  25. Cobb CA, Cole MP. Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis 2015, 84: 4–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 2006, 126: 2565–2575.

    Article  CAS  PubMed  Google Scholar 

  27. Chen Z, Zhong C. Oxidative stress in Alzheimer’s disease. Neurosci Bull 2014, 30: 271–281.

    Article  CAS  PubMed  Google Scholar 

  28. Wilson SR, Nelson AM, Batia L, Morita T, Estandian D, Owens DM, et al. The ion channel TRPA1 is required for chronic itch. J Neurosci 2013, 33: 9283–9294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu T, Han Q, Chen G, Huang Y, Zhao LX, Berta T, et al. Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain 2016, 157: 806–817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schlosburg JE, Boger DL, Cravatt BF, Lichtman AH. Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. J Pharmacol Exp Ther 2009, 329: 314–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular basis of itch sensation. Science 2009, 325: 1531–1534.

    Article  CAS  PubMed  Google Scholar 

  32. Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 2011, 14: 595–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang H, Li D, Hu Z, Zhao S, Zheng Z, Li W. Protective effects of green tea polyphenol against renal injury through ROS-mediated JNK-MAPK pathway in lead exposed rats. Mol Cells 2016, 39: 508–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pang XY, Liu T, Jiang F, Ji YH. Activation of spinal ERK signaling pathway contributes to pain-related responses induced by scorpion Buthus martensi Karch venom. Toxicon 2008, 51: 994–1007.

    Article  CAS  PubMed  Google Scholar 

  35. Zhao ZQ, Huo FQ, Jeffry J, Hampton L, Demehri S, Kim S, et al. Chronic itch development in sensory neurons requires BRAF signaling pathways. J Clin Invest 2013, 123: 4769–4780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang L, Jiang GY, Song NJ, Huang Y, Chen JY, Wang QX, et al. Extracellular signal-regulated kinase (ERK) activation is required for itch sensation in the spinal cord. Mol Brain 2014, 7: 25.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 1999, 2: 1114–1119.

    Article  CAS  PubMed  Google Scholar 

  38. Liu T, Gao YJ, Ji RR. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull 2012, 28: 131–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Baral P, Mills K, Pinho-Ribeiro FA, Chiu IM. Pain and itch: Beneficial or harmful to antimicrobial defense? Cell Host Microbe 2016, 19: 755–759.

    Article  CAS  PubMed  Google Scholar 

  40. Han SK, Mancino V, Simon MI. Phospholipase Cbeta 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons. Neuron 2006, 52: 691–703.

    Article  CAS  PubMed  Google Scholar 

  41. Mishra SK, Hoon MA. The cells and circuitry for itch responses in mice. Science 2013, 340: 968–971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci U S A 2009, 106: 11330–11335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ringkamp M, Schepers RJ, Shimada SG, Johanek LM, Hartke TV, Borzan J, et al. A role for nociceptive, myelinated nerve fibers in itch sensation. J Neurosci 2011, 31: 14841–14849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McNeil B, Dong X. Peripheral mechanisms of itch. Neurosci Bull 2012, 28: 100–110.

    Article  PubMed  Google Scholar 

  45. Shimizu K, Andoh T, Yoshihisa Y, Shimizu T. Histamine released from epidermal keratinocytes plays a role in alpha-melanocyte-stimulating hormone-induced itching in mice. Am J Pathol 2015, 185: 3003–3010.

    Article  CAS  PubMed  Google Scholar 

  46. Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007, 27: 2331–2337.

    Article  CAS  PubMed  Google Scholar 

  47. Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lu N, et al. TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest 2012, 122: 2195–2207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, et al. Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 2014, 82: 47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu T, Ji RR. New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflugers Arch 2013, 465: 1671–1685.

    Article  CAS  PubMed  Google Scholar 

  50. Akiyama T, Ivanov M, Nagamine M, Davoodi A, Carstens MI, Ikoma A, et al. Involvement of TRPV4 in Serotonin-Evoked Scratching. J Invest Dermatol 2016, 136: 154–160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen Y, Fang Q, Wang Z, Zhang JY, MacLeod AS, Hall RP, et al. Transient receptor potential vanilloid 4 ion channel functions as a pruriceptor in epidermal keratinocytes to evoke histaminergic itch. J Biol Chem 2016, 291: 10252–10262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Than JY, Li L, Hasan R, Zhang X. The excitation and modulation of TRPV1-, TRPA1-and TRPM8-expressing sensory neurons by the pruritogen chloroquine. J Biol Chem 2013, 288:12818–12827.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hoon MA. Molecular dissection of itch. Curr Opin Neurobiol 2015, 34: 61–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nashed MG, Balenko MD, Singh G. Cancer-induced oxidative stress and pain. Curr Pain Headache Rep 2014, 18: 384.

    Article  PubMed  Google Scholar 

  55. Chuang HH, Lin S. Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification. Proc Natl Acad Sci U S A 2009, 106: 20097–20102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Feldman EL. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 2003, 111: 431–433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee I, Kim HK, Kim JH, Chung K, Chung JM. The role of reactive oxygen species in capsaicin-induced mechanical hyperalgesia and in the activities of dorsal horn neurons. Pain 2007, 133: 9–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yosipovitch G, Carstens E, McGlone F. Chronic itch and chronic pain: Analogous mechanisms. Pain 2007, 131: 4–7.

    Article  PubMed  Google Scholar 

  59. Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 2007, 104: 13519–13524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Caceres AI, Brackmann M, Elia MD, Bessac BF, del CD, D’Amours M, et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci U S A 2009, 106: 9099–9104.

  61. Andersson DA, Gentry C, Moss S, Bevan S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 2008, 28: 2485–2494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nilius B, Appendino G, Owsianik G. The transient receptor potential channel TRPA1: from gene to pathophysiology. Pflugers Arch 2012, 464: 425–458.

    Article  CAS  PubMed  Google Scholar 

  63. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest 2008, 118: 1899–1910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 2006, 124: 1269–1282.

    Article  CAS  PubMed  Google Scholar 

  65. Linley JE, Ooi L, Pettinger L, Kirton H, Boyle JP, Peers C, et al. Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons. Proc Natl Acad Sci U S A 2012, 109: E1578–E1586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: Present concepts. J Gastroenterol Hepatol 2011, 26 Suppl 1: 173–179.

    Article  CAS  PubMed  Google Scholar 

  67. Kim HK, Park SK, Zhou JL, Taglialatela G, Chung K, Coggeshall RE, et al. Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain 2004, 111: 116–124.

    Article  CAS  PubMed  Google Scholar 

  68. Jiang GY, Dai MH, Huang K, Chai GD, Chen JY, Chen L, et al. Neurochemical characterization of pERK-expressing spinal neurons in histamine-induced itch. Sci Rep 2015, 5: 12787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31371179 and 81300968), and from the Natural Science Foundation of Jiangsu Province, China (BK20140372). TL was supported by funding from Jiangsu Province, China (2015-JY-029). SW was also supported by a grant from Jiangsu Province, China (201310285096X). This work is subject to the second affiliated hospital of Soochow University Preponderant Clinic Discipline Group Project Funding (XKQ2015007) and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. We are grateful to Fei Xiong, Cheng-Ting Feng, Xia Wang, and Xiao-Ting Shi for excellent technical assistance.

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    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

      Feng-Ming Zhou, Ruo-Xiao Cheng, Shuai Wang & Tong Liu

    2. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, 215123, China

      Shuai Wang & Li-Hua Chen

    3. Institute of Neuroscience, Soochow University, Suzhou, 215123, China

      Feng-Ming Zhou, Ruo-Xiao Cheng, Ya Huang, Yan Zhou, Teng-Teng Liu & Tong Liu

    4. Institute of Nautical Medicine, Nantong University, Nantong, 226001, China

      Yong-Jing Gao

    5. Beijing Electric Power Hospital, Beijing, 100073, China

      Xue-Long Wang

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    Feng-Ming Zhou and Ruo-Xiao Cheng have contributed equally to this work.

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    Zhou, FM., Cheng, RX., Wang, S. et al. Antioxidants Attenuate Acute and Chronic Itch: Peripheral and Central Mechanisms of Oxidative Stress in Pruritus. Neurosci. Bull. 33, 423–435 (2017). https://doi.org/10.1007/s12264-016-0076-z

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