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Nicotine exerts neuroprotective effects by attenuating local inflammatory cytokine production following crush injury to rat sciatic nerves

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European Cytokine Network Aims and scope

Abstract

Background

Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats.

Methods

Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1β), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves.

Results

Treatment with nicotine decreased local levels of TNF-α and IL-1β, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR.

Conclusion

These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.

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References

  1. Vaz KM, Brown JM, Shah SB. Peripheral nerve lengthening as a regenerative strategy. Neural Regen Res 2014; 9: 1498–501.

    Article  Google Scholar 

  2. Fawcett JW, Keynes RJ. Peripheral nerve regeneration. Annu Rev Neurosci 1990; 13: 43–60.

    Article  CAS  Google Scholar 

  3. Valero-Cabre A, Tsironis K, Skouras E, Navarro X, Neiss WF. Peripheral and spinal motor reorganization after nerve injury and repair. J Neurotrauma 2004; 21: 95–108.

    Article  Google Scholar 

  4. Rosberg HE, Carlsson KS, Hojgard S, Lindgren B, Lundborg G, Dahlin LB. Injury to the human median and ulnar nerves in the forearm - analysis of costs for treatment and rehabilitation of 69 patients in southern Sweden. J Hand Surg 2005; 30: 35–9.

    Article  CAS  Google Scholar 

  5. Stoll G, Jander S, Myers RR. Degeneration and regeneration of the peripheral nervous system: from Augustus Waller’s observations to neuroinflammation. J Peripher Nerv Syst 2002; 7: 13–27.

    Article  Google Scholar 

  6. Hall S. The response to injury in the peripheral nervous system. J Bone Joint Surg Br 2005; 87: 1309–19.

    Article  CAS  Google Scholar 

  7. 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: 215–9.

    Article  CAS  Google Scholar 

  8. Kato N, Matsumoto M, Kogawa M, et al. Critical role of p38 MAPK for regeneration of the sciatic nerve following crush injury in vivo. J Neuroinflammation 2013; 10: 1.

    Article  CAS  Google Scholar 

  9. Feng Y, Yang Q, Xu J, et al. Preparation and identification of the lipopolysaccharide binding protein mimic epitope peptide vaccine that prevents endotoxin-induced acute lung injury in mice. Vaccine 2011; 29: 4162–72.

    Article  CAS  Google Scholar 

  10. Kato K, Liu H, Kikuchi S, Myers RR, Shubayev VI. Immediate anti-tumor necrosis factor-alpha (etanercept) therapy enhances axonal regeneration after sciatic nerve crush. J Neurosci Res 2010; 88: 360–8.

    Article  CAS  Google Scholar 

  11. Hiemke C, Stolp M, Reuss S, et al. Expression of alpha subunit genes of nicotinic acetylcholine receptors in human lymphocytes. Neurosci Lett 1996; 214: 171–4.

    Article  CAS  Google Scholar 

  12. Drescher DG, Khan KM, Green GE, et al. Analysis of nicotinic acetylcholine receptor subunits in the cochlea of the mouse. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1995; 112: 267–73.

    Article  CAS  Google Scholar 

  13. Mabley J, Gordon S, Pacher P. Nicotine exerts an antiinflammatory effect in a murine model of acute lung injury. Inflammation 2011; 34: 231–7.

    Article  CAS  Google Scholar 

  14. Sadis C, Teske G, Stokman G, et al. Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway. PLoS One 2007; 2: e469.

    Article  Google Scholar 

  15. Guan YZ, Jin XD, Guan LX, et al. Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Mol Neurobiol 2015; 51(3):1480–8.

    Article  CAS  Google Scholar 

  16. Ravikumar R, Flora G, Geddes JW, Hennig B, Toborek M. Nicotine attenuates oxidative stress, activation of redoxregulated transcription factors and induction of proinflammatory genes in compressive spinal cord trauma. Brain Res Mol Brain Res 2004; 124: 188–98.

    Article  CAS  Google Scholar 

  17. Crockett ET, Galligan JJ, Uhal BD, Harkema J, Roth R, Pandya K. Protection of early phase hepatic ischemiareperfusion injury by cholinergic agonists. BMC Clin Pathol 2006; 6: 3.

    Article  Google Scholar 

  18. Ni YF, Tian F, Lu ZF, et al. Protective effect of nicotine on lipopolysaccharide-induced acute lung injury in mice. Respiration 2011; 81: 39–46.

    Article  CAS  Google Scholar 

  19. Garrido R, King-Pospisil K, Son KW, Hennig B, Toborek M. Nicotine upregulates nerve growth factor expression and prevents apoptosis of cultured spinal cord neurons. Neurosci Res 2003; 47: 349–55.

    Article  CAS  Google Scholar 

  20. Thornton MR, Mantovani C, Birchall MA, Terenghi G. Quantification of N-CAM and N-cadherin expression in axotomized and crushed rat sciatic nerve. J Anat 2005; 206: 69–78.

    Article  CAS  Google Scholar 

  21. George A, Schmidt C, Weishaupt A, Toyka KV, Sommer C. Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp Neurol 1999; 160: 124–32.

    Article  CAS  Google Scholar 

  22. McQuarrie IG, Grafstein B, Gershon MD. Axonal regeneration in the rat sciatic nerve: effect of a conditioning lesion and of dbcAMP. Brain Res 1977; 132: 443–53.

    Article  CAS  Google Scholar 

  23. Sacharuk VZ, Lovatel GA, Ilha J, et al. Thermographic evaluation of hind paw skin temperature and functional recovery of locomotion after sciatic nerve crush in rats. Clinics 2011; 66: 1259–66.

    Article  Google Scholar 

  24. Shen CC, Yang YC, Huang TB, Chan SC, Liu BS. Low-level laser-accelerated peripheral nerve regeneration within a reinforced nerve conduit across a large gap of the transected sciatic nerve in rats. Evid Based Complement Altern Med: eCAM 2013; 2013: 175629.

    Google Scholar 

  25. Wang D, Wang X, Geng S, Bi Z. Axonal regeneration in early stages of sciatic nerve crush injury is enhanced by alpha7nAChR in rats. Mol Biol Rep 2014; 42: 603–9.

    Article  Google Scholar 

  26. Seijffers R, Mills CD, Woolf CJ. ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration. J Neurosci 2007; 27: 7911–20.

    Article  CAS  Google Scholar 

  27. Zou DW, Gao YB, Zhu ZY, et al. Traditional Chinese medicine tang-luo-ning ameliorates sciatic nerve injuries in streptozotocin-induced diabetic rats. Evid Based Complement Altern Med: eCAM 2013; 2013: 989670.

    Google Scholar 

  28. Navarro X, Vivo M, Valero-Cabre A. Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol 2007; 82: 163–201.

    Article  CAS  Google Scholar 

  29. Kummer W, Lips KS, Pfeil U. The epithelial cholinergic system of the airways. Histochem Cell Biol 2008; 130: 219–34.

    Article  CAS  Google Scholar 

  30. Xiu J, Nordberg A, Zhang JT, Guan ZZ. Expression of nicotinic receptors on primary cultures of rat astrocytes and up-regulation of the alpha7, alpha4 and beta2 subunits in response to nanomolar concentrations of the beta-amyloid peptide (1-42). Neurochem Int 2005; 47: 281–90.

    Article  CAS  Google Scholar 

  31. Liu RH, Mizuta M, Matsukura S. The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. J Pharmacol Exp Ther 2004; 310: 52–8.

    Article  CAS  Google Scholar 

  32. Kurzen H, Wessler I, Kirkpatrick CJ, Kawashima K, Grando SA. The non-neuronal cholinergic system of human skin. Horm Metab Res 2007; 39: 125–35.

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from the Science and Technology Innovation Talent Research Special fund Youth Talent Project of Harbin (2017RAQYJ160).

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Correspondence to Dewei Wang.

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Wang, D., Gao, T., Zhao, Y. et al. Nicotine exerts neuroprotective effects by attenuating local inflammatory cytokine production following crush injury to rat sciatic nerves. Eur Cytokine Netw 30, 59–66 (2019). https://doi.org/10.1684/ecn.2019.0426

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  • DOI: https://doi.org/10.1684/ecn.2019.0426

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