Skip to main content

Advertisement

SpringerLink
Log in

Axonal protection achieved in a model of multiple sclerosis using lamotrigine

  • ORIGINAL COMMUNICATION
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Axonal degeneration is a major cause of permanent disability in multiple sclerosis (MS). Recent observations from our and other laboratories suggest that sodium accumulation within compromised axons is a key, early step in the degenerative process, and hence that limiting axonal sodium influx may represent a mechanism for axonal protection in MS. Here we assess whether lamotrigine, a sodium channel-blocking agent, is effective in preventing axonal degeneration in an animal model of MS, namely chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE). When administered from 7 days post-inoculation, lamotrigine provided a small but significant reduction in the neurological deficit present at the termination of the experiments (averaged over three independent experiments; vehicle: 3.5 ± 2.7; lamotrigine: 2.6 ± 2.0, P < 0.05) and preserved more functional axons in the spinal cord (measured as mean compound action potential area; vehicle: 31.7 μV.ms ± 23.0; lamotrigine: 42.9 ± 27.4, P < 0.05). Histological examination of the thoracic spinal cord (n = 71) revealed that lamotrigine treatment also provided significant protection against axonal degeneration (percentage degeneration in dorsal column; vehicle: 33.5 % ± 38.5; lamotrigine: 10.4 % ± 12.5, P < 0.01). The findings suggest that lamotrigine may provide a novel avenue for axonal protection in MS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A, Bruck W, Lucchinetti C, Schmidbauer M, Jellinger K, Lassmann H (2003) Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J Neuropathol Exp Neurol 62:25–33

    PubMed  CAS  Google Scholar 

  2. Ahern GP, Hsu SF, Klyachko VA, Jackson MB (2000) Induction of persistent sodium current by exogenous and endogenous nitric oxide. J Biol Chem 275:28810–28815

    Article  PubMed  CAS  Google Scholar 

  3. Bechtold DA, Hasoon P, Smith KJ (2004) Sodium channel blockade reduces spinal cord inflammation during EAE. Soc Neuroscience, Online program 936.3 (Abstract)

  4. Bechtold DA, Kapoor R, Smith KJ (2004) Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol 55:607–616

    Article  PubMed  CAS  Google Scholar 

  5. Bechtold DA, Smith KJ (2005) Sodium-mediated axonal degeneration in inflammatory demyelinating disease. J Neurol Sci 233:27–35

    Article  PubMed  CAS  Google Scholar 

  6. Bechtold DA, Yue X, Evans RM, Davies M, Gregson NA, Smith KJ (2005) Axonal protection in experimental autoimmune neuritis by the sodium channel blocking agent flecainide. Brain 128:18–28

    Article  PubMed  Google Scholar 

  7. Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48:893–901

    Article  PubMed  CAS  Google Scholar 

  8. Bjartmar C, Wujek JR, Trapp BD (2003) Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 206:165–171

    Article  PubMed  CAS  Google Scholar 

  9. Black JA, Dib-Hajj S, Baker D, Newcombe J, Cuzner ML, Waxman SG (2000) Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Proc Natl Acad Sci U S A 97:11598–11602

    Article  PubMed  CAS  Google Scholar 

  10. Bolanos JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB, Heales SJ (1997) Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 68:2227–2240

    Article  PubMed  CAS  Google Scholar 

  11. Calabresi P, Centonze D, Marfia GA, Pisani A, Bernardi G (1999) An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons. Br J Pharmacol 126:689–696

    Article  PubMed  CAS  Google Scholar 

  12. Craner MJ, Damarjian TG, Liu S, Hains BC, Lo AC, Black JA, Newcombe J, Cuzner ML, Waxman SG (2005) Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49:220–229

    Article  PubMed  Google Scholar 

  13. Craner MJ, Hains BC, Lo AC, Black JA, Waxman SG (2004) Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 127:294–303

    Article  PubMed  Google Scholar 

  14. Craner MJ, Lo AC, Black JA, Waxman SG (2003) Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain 126:1552–1561

    Article  PubMed  Google Scholar 

  15. Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG (2004) Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci U S A 101:8168–8173

    Article  PubMed  CAS  Google Scholar 

  16. Davie CA, Barker GJ, Webb S, Tofts PS, Thompson AJ, Harding AE, McDonald WI, Miller DH (1995) Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 118:1583–1592

    Article  PubMed  Google Scholar 

  17. DeLuca GC, Ebers GC, Esiri MM (2004) Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 127:1009–1018

    Article  PubMed  CAS  Google Scholar 

  18. Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM (2000) Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 123:1845–1849

    Article  PubMed  Google Scholar 

  19. Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399

    Article  PubMed  Google Scholar 

  20. Filippi M, Campi A, Martinelli V, Colombo B, Scotti G, Comi G (1996) Brain and spinal cord MR in benign multiple sclerosis: a follow-up study. J Neurol Sci 143:143–149

    Article  PubMed  CAS  Google Scholar 

  21. Gallin EK (1991) Ion channels in leukocytes. Physiol Rev 71:775–811

    PubMed  CAS  Google Scholar 

  22. Garthwaite G, Goodwin DA, Batchelor AM, Leeming K, Garthwaite J (2002) Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience 109:145–155

    Article  PubMed  CAS  Google Scholar 

  23. Graumann U, Reynolds R, Steck AJ, Schaeren-Wiemers N (2003) Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol 13:554–573

    Article  PubMed  CAS  Google Scholar 

  24. Hammarstrom AK, Gage PW (2002) Hypoxia and persistent sodium current. Eur Biophys J 31:323–330

    Article  PubMed  CAS  Google Scholar 

  25. Hammarstrom AK, Gage PW (1999) Nitric oxide increases persistent sodium current in rat hippocampal neurons. J Physiol 520:451–461

    Article  PubMed  CAS  Google Scholar 

  26. Hewitt KE, Stys PK, Lesiuk HJ (2001) The use-dependent sodium channel blocker mexiletine is neuroprotective against global ischemic injury. Brain Res 898:281–287

    Article  PubMed  CAS  Google Scholar 

  27. Horn EM, Waldrop TG (2000) Hypoxic augmentation of fast-inactivating and persistent sodium currents in rat caudal hypothalamic neurons. J Neurophysiol 84:2572–2581

    PubMed  CAS  Google Scholar 

  28. Kalkers NF, Bergers E, Castelijns JA, van Walderveen MA, Bot JC, Ader HJ, Polman CH, Barkhof F (2001) Optimizing the association between disability and biological markers in MS. Neurology 57:1253–1258

    PubMed  CAS  Google Scholar 

  29. Kapoor R, Davies M, Blaker PA, Hall SM, Smith KJ (2003) Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol 53:174–180

    Article  PubMed  CAS  Google Scholar 

  30. Khan NA, Poisson JP (1999) 5-HT3 receptor-channels coupled with Na+ influx in human T cells: role in T cell activation. J Neuroimmunol 99:53–60

    Article  PubMed  CAS  Google Scholar 

  31. Kuo CC (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol Pharmacol 54:712–721

    PubMed  CAS  Google Scholar 

  32. Kuo CC, Lu L (1997) Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurones. Br J Pharmacol 121:1231–1238

    Article  PubMed  CAS  Google Scholar 

  33. Lai ZF, Chen YZ, Nishimura Y, Nishi K (2000) An amiloride-sensitive and voltage-dependent Na+ channel in an HLA-DR-restricted human T cell clone. J Immunol 165:83–90

    PubMed  CAS  Google Scholar 

  34. Lang DG, Wang CM, Cooper BR (1993) Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J Pharmacol Exp Ther 266:829–835

    PubMed  CAS  Google Scholar 

  35. Lees G, Leach MJ (1993) Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neurological cultures from rat cortex. Brain Res 612:190–199

    Article  PubMed  CAS  Google Scholar 

  36. Lehning EJ, Doshi R, Stys PK, LoPachin RM, Jr. (1995) Mechanisms of injury-induced calcium entry into peripheral nerve myelinated axons: in vitro anoxia and ouabain exposure. Brain Res 694:158–166

    Article  PubMed  CAS  Google Scholar 

  37. Lo AC, Saab CY, Black JA, Waxman SG (2003) Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J Neurophysiol 90:3566–3571

    Article  PubMed  CAS  Google Scholar 

  38. Losseff NA, Wang L, Lai HM, Yoo DS, Gawne-Cain ML, McDonald WI, Miller DH, Thompson AJ (1996) Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain 119:2009–2019

    PubMed  Google Scholar 

  39. Losseff NA, Webb SL, O’Riordan JI, Page R, Wang L, Barker GJ, Tofts PS, McDonald WI, Miller DH, Thompson AJ (1996) Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 119:701–708

    PubMed  Google Scholar 

  40. Lunardi G, Leandri M, Albano C, Cultrera S, Fracassi M, Rubino V, Favale E (1997) Clinical effectiveness of lamotrigine and plasma levels in essential and symptomatic trigeminal neuralgia. Neurology 48:1714–1717

    PubMed  CAS  Google Scholar 

  41. Makowska A, Bechtold DA, Sajic M, Gregson NA, Hughes RA, Smith KJ (2004) Sodium channel blocking agents affect T cell function. J Neuroimmunol 154:88 (Abstract)

    Google Scholar 

  42. McCleane G (1998) Lamotrigine can reduce neurogenic pain associated with multiple sclerosis. Clin J Pain 14:269–270

    Article  PubMed  CAS  Google Scholar 

  43. Medana IM, Esiri MM (2003) Axonal damage: a key predictor of outcome in human CNS diseases. Brain 126:515–530

    Article  PubMed  CAS  Google Scholar 

  44. Metz L (1998) Multiple sclerosis: symptomatic therapies. Semin Neurol 18:389–395

    Article  PubMed  CAS  Google Scholar 

  45. Pitt D, Werner P, Raine CS (2000) Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 6:67–70

    Article  PubMed  CAS  Google Scholar 

  46. Redford EJ, Hall SM, Smith KJ (1995) Vascular changes and demyelination induced by the intraneural injection of tumour necrosis factor. Brain 118:869–878

    Article  PubMed  Google Scholar 

  47. Rush AM, Dib-Hajj SD, Waxman SG (2005) Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones. J Physiol 564:803–815

    Article  PubMed  CAS  Google Scholar 

  48. Sakurai M, Kanazawa I (1999) Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletine. J Neurol Sci 162:162–168

    Article  PubMed  CAS  Google Scholar 

  49. Sakurai M, Mannen T, Kanazawa I, Tanabe H (1992) Lidocaine unmasks silent demyelinative lesions in multiple sclerosis. Neurology 42:2088–2093

    PubMed  CAS  Google Scholar 

  50. Smith KJ, Kapoor R, Hall SM, Davies M (2001) Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 49:470–476

    Article  PubMed  CAS  Google Scholar 

  51. Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1:232–241

    Article  PubMed  CAS  Google Scholar 

  52. Smith KJ, McDonald WI (1999) The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philos Trans R Soc Lond B Biol Sci 354:1649–1673

    Article  PubMed  CAS  Google Scholar 

  53. Smith T, Groom A, Zhu B, Turski L (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6:62–66

    Article  PubMed  CAS  Google Scholar 

  54. Stefani A, Spadoni F, Bernardi G (1997) Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies. Exp Neurol 147:115–122

    Article  PubMed  CAS  Google Scholar 

  55. Stevenson VL, Leary SM, Losseff NA, Parker GJ, Barker GJ, Husmani Y, Miller DH, Thompson AJ (1998) Spinal cord atrophy and disability in MS: a longitudinal study. Neurology 51:234–238

    PubMed  CAS  Google Scholar 

  56. Stys PK (1998) Anoxic and ischemic injury of myelinated axons in CNS white matter: from mechanistic concepts to therapeutics. J Cereb Blood Flow Metab 18:2–25

    Article  PubMed  CAS  Google Scholar 

  57. Stys PK, Lopachin RM (1998) Mechanisms of calcium and sodium fluxes in anoxic myelinated central nervous system axons. Neuroscience 82:21–32

    Article  PubMed  CAS  Google Scholar 

  58. Stys PK, Waxman SG, Ransom BR (1992) Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. J Neurosci 12:430–439

    PubMed  CAS  Google Scholar 

  59. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285

    Article  PubMed  CAS  Google Scholar 

  60. Trapp BD, Ransohoff R, Rudick R (1999) Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 12:295–302

    Article  PubMed  CAS  Google Scholar 

  61. Wang SJ, Huang CC, Hsu KS, Tsai JJ, Gean PW (1996) Inhibition of N-type calcium currents by lamotrigine in rat amygdalar neurones. Neuroreport 7:3037–3040

    Article  PubMed  CAS  Google Scholar 

  62. Waxman SG (2003) Nitric oxide and the axonal death cascade. Ann Neurol 53:150–153

    Article  PubMed  Google Scholar 

  63. Waxman SG (2004) Gifts from the molecular revolution: protection and repair of the injured spinal cord. J Spinal Cord Med 27:304–310

    PubMed  Google Scholar 

  64. Wujek JR, Bjartmar C, Richer E, Ransohoff RM, Yu M, Tuohy VK, Trapp BD (2002) Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J Neuropathol Exp Neurol 61:23–32

    PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Mr. Meirion Davies, Ms. Clare Farmer, Mr. Matthew Smith and Dr. Marija Sajic for technical assistance relating to this work. Lamotrigine was kindly provided by GlaxoSmithKline. The work was supported by grants from the Multiple Sclerosis Society of Great Britain and Northern Ireland, a PhD studentship (to DAB) from King’s College, and a bursary (to ACD) from the Health Foundation.

Author information

Authors and Affiliations

  1. Dept. of Clinical Neuroscience, King’s College London, Guy’s Campus, London, UK

    David A. Bechtold, Sandra J. Miller, Angela C. Dawson, Yue Sun, Raju Kapoor & Kenneth J. Smith

  2. National Hospital for Neurology and Neurosurgery, London, UK

    Raju Kapoor

  3. Medical Toxicology Unit, Guy’s and St Thomas’ Trust, London, UK

    David Berry

Authors
  1. David A. Bechtold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra J. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela C. Dawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yue Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raju Kapoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Berry
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenneth J. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth J. Smith.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bechtold, D.A., Miller, S.J., Dawson, A.C. et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol 253, 1542–1551 (2006). https://doi.org/10.1007/s00415-006-0204-1

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-006-0204-1

Keywords

Search

Navigation