Analysis of the dose-response of N-acetylcysteine in the prevention of sensory neuronal loss after peripheral nerve injury

  • C. A. West
  • A. M. Hart1
  • G. Terenghi
  • M. Wiberg
Part of the Acta Neurochirurgica Supplementum book series (NEUROCHIRURGICA, volume 100)



N-Acetylcysteine (NAC) is a safe pharmaceutical agent known to protect cells from oxidative damage. Following peripheral nerve transection, NAC has been found to eliminate sensory neuronal loss. This study examines the dose-response relationship of NAC in preventing neuronal death.

Methods and Findings

The rat sciatic nerve transection model was used, and stereological quantification of sensory neuron survival carried out at two weeks post-axotomy. NAC was administered systemically as an intraperitoneal injection to five groups of rats at a range of doses (1-300 mg/kg/day). Significant neuronal loss was observed in the 1 mg/kg/day dosage group (18.5% loss, p = 0.067 vs. sham treatment). A degree of neuroprotection occurred with 10 mg/kg/day (9.1% loss, p < 0.005 vs. control), whilst there was no significant loss with either 150 or 300 mg/kg/day.


The prevention of sensory neuronal loss with NAC is dose dependent and effective over a wide therapeutic range. This analysis confirms the efficacy of systemic administration and provides a dose framework with which NAC has clinical potential to improve outcome after peripheral nerve trauma.


N-Acetylcysteine nerve injury axotomy neuroprotection optical fractionator dorsal root ganglia 


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  1. 1.
    Corcoran GB, Wong BK (1986) Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice. J Pharmacol Exp Ther 238(1): 54–61PubMedGoogle Scholar
  2. 2.
    Cotgreave IA, Berggren M, Jones TW, Dawson J, Moldeus P (1987) Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems. Biopharm Drug Dispos 8(4): 377–386PubMedCrossRefGoogle Scholar
  3. 3.
    Dyck PJ, Peroutka S, Rask C, Burton E, Baker MK, Lehman KA et al (1997) Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans. Neurology 48(2): 501–505PubMedGoogle Scholar
  4. 4.
    Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14(1–2): 67–116PubMedCrossRefGoogle Scholar
  5. 5.
    Hart AM, Terenghi G, Kellerth JO, Wiberg M (2004) Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury. Neuroscience 125(1): 91–101PubMedCrossRefGoogle Scholar
  6. 6.
    Hart AM, Terenghi G (2004) Frozen-section fluorescence microscopy and stereology in the quantification of neuronal death within dorsal root ganglia. J Mol Histol 35(6): 565–580PubMedCrossRefGoogle Scholar
  7. 7.
    Kallio PK, Vastamaki M, Solonen KA (1993) The results of secondary microsurgical repair of radial nerve in 33 patients. J Hand Surg [Br] 18(3): 320–322CrossRefGoogle Scholar
  8. 8.
    Lundborg G (2000) A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical significance. J Hand Surg [Am] 25(3): 391–414Google Scholar
  9. 9.
    Mant TG, Tempowski JH, Volans GN, Talbot JC (1984) Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed) 289(6439): 217–219Google Scholar
  10. 10.
    Martin D, Merkel E, Tucker KK, McManaman JL, Albert D, Relton J et al (1996) Cachectic effect of ciliary neurotrophic factor on innervated skeletal muscle. Am J Physiol 271(5 Pt 2): R1422–R1428PubMedGoogle Scholar
  11. 11.
    McArthur JC, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H et al (2000) A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 54(5): 1080–1088PubMedGoogle Scholar
  12. 12.
    McKay HA, Brannstrom T, Wiberg M, Terenghi G (2002) Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat: timecourse of cell death and elimination. Exp Brain Res 142(3): 308–318CrossRefGoogle Scholar
  13. 13.
    Novikova LN, Novikov LN, Kellerth JO (2000) BDNF abolishes the survival effect of NT-3 in axotomized clarke neurons of adult rats. J Comp Neurol 428(4): 671–680PubMedCrossRefGoogle Scholar
  14. 14.
    Novikova LN, Novikov LN, Kellerth JO (2000) Survival effects of BDNF and NT-3 on axotomized rubrospinal neurons depend on the temporal pattern of neurotrophin administration. Eur J Neurosci 12(2): 776–780PubMedCrossRefGoogle Scholar
  15. 15.
    Prescott LF, Donovan JW, Jarvie DR, Proudfoot AT (1989) The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage. Eur J Clin Pharmacol 37(5): 501–506PubMedCrossRefGoogle Scholar
  16. 16.
    Tandrup T, Woolf CJ, Coggeshall RE (2000) Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve. J Comp Neurol 422(2): 172–180PubMedCrossRefGoogle Scholar
  17. 17.
    Terenghi G (1999) Peripheral nerve regeneration and neurotrophic factors. J Anat 194 (Pt 1): 1–14PubMedCrossRefGoogle Scholar
  18. 18.
    Wiberg M, Hazari A, Ljungberg C, Pettersson K, Backman C, Nordh E et al (2003) Sensory recovery after hand reimplantation: a clinical, morphological, and neurophysiological study in humans. Scand J Plast Reconstr Surg Hand Surg 37(3): 163–173PubMedCrossRefGoogle Scholar
  19. 19.
    Wilson DH, Hart A, Brannstrom T, Wiberg M, Terenghi G (2007) Delayed acetyl-L-carnitine administration and its effect on sensory neuronal rescue after peripheral nerve injury. J Plast Reconstr Aesthet Surg 60: 114–118PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang C-G, Welin D, Novikov L, Kellerth J-O, Wiberg M, Hart A (2005) Motorneuron protection by N-acetyl-cysteine after ventral root avulsion and ventral rhizotomy. Br J Plast Surg 58: 765–773PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • C. A. West
    • 2
    • 3
  • A. M. Hart1
    • 2
    • 5
  • G. Terenghi
    • 1
  • M. Wiberg
    • 3
    • 4
  1. 1.Blond McIndoe Research Laboratories 3.102 Stopford BuildingUniversity of ManchesterManchesterUK
  2. 2.Blond McIndoe Research LaboratoriesUniversity of ManchesterManchesterUK
  3. 3.Department of Integrative Medical Biology, Section for AnatomyUmeå UniversityUmeåSweden
  4. 4.Department of Surgical and Perioperative Science, Section for Hand and Plastic SurgeryUniversity HospitalUmeåSweden
  5. 5.Canniesburn Plastic Surgery UnitGlasgow Royal InfirmaryGlasgowUK

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