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Axonal Protection with Sodium Channel Blocking Agents in Models of Multiple Sclerosis

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Myelin Repair and Neuroprotection in Multiple Sclerosis

Abstract

Axonal degeneration in multiple sclerosis (MS) has come to be increasingly appreciated as a major contributor to nonremitting disability in MS. Significant axonal damage and loss occur with acute MS plaques, and this loss continues, albeit at an attenuated rate, in chronic inactive plaques. These observations have triggered considerable interest in identifying neuroprotective therapies that can ameliorate axonal injury and degeneration in neuroinflammatory disorders. Accumulating evidence implicates participation of voltage-gated sodium channels in Ca2+-mediated damage of central white matter axons. Indeed, blockade of sodium channels has been shown to provide protective effects for axons exposed to anoxia, trauma, and ischemia injuries. In the present chapter, we describe work from our laboratories that has examined the effects of sodium channel blocking agents on disease progression in rodent models of neuroinflammatory lesions, including experimental autoimmune encephalomyelitis (EAE), a disease that is widely utilized to model aspects of MS. The sodium channel blocking agents utilized in our studies—phenytoin, carbamazepine, flecainide, and lamotrigine—provide robust protection of spinal cord axons, preserve action potential conduction, significantly diminish immune cell infiltration, and attenuate neurological deficits in EAE. Results from these studies provided a rationale for planning and implementing clinical studies utilizing sodium channel blocking agents in patients with MS, and several clinical trials examining the efficacy of sodium channel blockade in ameliorating clinical disability in MS are currently ongoing.

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References

  • Aboul-Enein F, Lassmann H (2005) Mitochondrial damage and histotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease? Acta Neuropathol 109:49–55

    Article  PubMed  CAS  Google Scholar 

  • Agrawal SK, Fehlings MG (1996) Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na+-K+-ATPase, the Na+-H+ exchanger, and the Na+-Ca2+ exchanger. J Neurosci 16:545–552

    PubMed  CAS  Google Scholar 

  • Andrade-Mena CE, Sardo-Olmedo JAJ, Ramirez-Lizardo EJ (1994) Effects of phenytoin administration on murine immune function. J Neuroimmunol 50:3–7

    Article  PubMed  CAS  Google Scholar 

  • Bechtold DA (2004) Axonal protection in experimental models of inflammatory demyelinating disease. PhD Thesis, University of London

    Google Scholar 

  • Bechtold DA, Kapoor R, Smith KJ (2002) Axonal protection mediated by flecainide therapy in experimental inflammatory demyelinating disease. J Neurol 249(suppl 1):204

    Google Scholar 

  • 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 

  • 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 

  • Bechtold DA, Miller SJ, Dawson AC, Sun Y, Kapoor R, Berry D, Smith KJ (2006) Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol 253:1542–1551

    Article  PubMed  Google Scholar 

  • Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, BrĂĽck W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123:1174–1183

    Article  PubMed  Google Scholar 

  • Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, BrĂĽck W (2001) A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol 49(6):793–796

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Bjartmar C, Kinkel RP, Kidd G, Rudick RA, Trapp BD (2001) Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 57(7):1248–1252

    Article  PubMed  CAS  Google Scholar 

  • Black JA, Liu S, Hains BC, Saab CY, Waxman SG (2006) Longterm protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain 129:3196–3208

    Article  PubMed  Google Scholar 

  • Black JA, Liu S, Carrithers M, Carrithers LM, Waxman SG (2007) Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann Neurol 67:21–33

    Article  Google Scholar 

  • Black JA, Liu S, Waxman SG (2009) Sodium channel activity modulates multiple functions in microglia. Glia 57(10):1072–1081

    Article  PubMed  Google Scholar 

  • Bo L, Dawson TM, Wesselingh S, Mork S, Choi S, Kong PA, Hanley D, Trapp BD (1994) Induction of nitric oxide synthetase in demyelinating regions of multiple sclerosis. Ann Neurol 36:78–786

    Article  Google Scholar 

  • Brosnan CF, Battistini L, Raine C, Dickson DW, Casadevall A (1994) Reactive nitrogen intermediates in human neuropathology: an overview. Dev Neurosci 16:152–161

    Article  PubMed  CAS  Google Scholar 

  • Brown GC (2007) Nitric oxide and mitochondria. Front Biosci 12:1024–1033

    Article  PubMed  CAS  Google Scholar 

  • Brown AM, McFarlin DE (1981) Relapsing experimental allergic encephalomyelitis in the SJL/J mouse. Lab Invest 45(3):278–284

    PubMed  CAS  Google Scholar 

  • Carrithers MD, Dib-Hajj S, Carrithers LM, Tokmoulina G, Pypaert M, Jonas EA, Waxman SG (2007) Expression of the voltage-gated sodium channel Nav1.5 in the macrophage late endosome regulates endosomal acidification. J Immunol 178:7822–7832

    PubMed  CAS  Google Scholar 

  • Carrithers MD, Chatterjee G, Carrithers LM, Offoha R, Iheagwara U, Rahner R, Graham M, Waxman SG (2009) Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A. J Biol Chem 284(12):8114–8126

    Article  PubMed  CAS  Google Scholar 

  • Charcot M (1868) Histologie de la sclerose en plaques. Gaz Hosp 141(554–5):557–558

    Google Scholar 

  • Craner MC, 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 

  • DeCoursey TE, Chandy KG, Gupta S et al (1985) Voltage-dependent ion channels in T-lymphocytes. J Neuroimmunol 10:71–95

    Article  PubMed  CAS  Google Scholar 

  • DeLuca GC, Ebers GC, Esiri MM (2004) The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol 30(6):576–584

    Article  PubMed  CAS  Google Scholar 

  • DeStefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121:1469–1477

    Article  Google Scholar 

  • DeStefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58(1):65–70

    Article  CAS  Google Scholar 

  • Dutta R, Trapp BD (2007) Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 68(22 Suppl 3):S22–S31

    Article  PubMed  Google Scholar 

  • Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489

    Article  PubMed  CAS  Google Scholar 

  • Eder C (1998) Ion channels in microglia (brain macrophages). Am J Physiol 275:C327–C342

    PubMed  CAS  Google Scholar 

  • Evangelou N, Esiri MM, Smith S, Palace J, Matthews PM (2000) Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 47(3):391–395

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Fern R, Ransom BR, Stys PK, Waxman SG (1993) Pharmacological protection of CNS white matter during anoxia: actions of phenytoin, carbamazepine, and diazepam. J Pharmacol Exp Ther 266:1549–1555

    PubMed  CAS  Google Scholar 

  • Fraser SP, Diss JKJ, Lloyd LJ et al (2004) T-lymphocyte invasiveness: control by voltage-gated Na+ channel activity. FEBS Lett 569:191–194

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ganter P, Prince C, Esiri MM (1999) Spinal cord axonal loss in multiple sclerosis: a post-mortem study. Neuropathol Appl Neurobiol 25(6):459–467

    Article  PubMed  CAS  Google Scholar 

  • Garthwaite G, Goodin 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 

  • Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953–1971

    Article  PubMed  Google Scholar 

  • Hains BC, Waxman SG (2005) Neuroprotection by sodium channel blockade with phenytoin in an experimental model of glaucoma. Invest Ophthalmol Vis Sci 46(11):4164–4169

    Article  PubMed  Google Scholar 

  • Hains BC, Saab CY, Lo AC, Waxman SG (2004) Sodium channel blockade with phenytoin protects spinal cord axons, enhances axonal conduction, and improves functional motor recovery after contusion SCI. Exp Neurol 188:365–377

    Article  PubMed  CAS  Google Scholar 

  • Hewitt KE, Stys PK, Lesiuk HJ (2001) The use-dependent sodium channel blocker mexiletine is neuroprotective against global ischemic injury. Brain Res 898(2):281–287

    Article  PubMed  CAS  Google Scholar 

  • Imaizumi T, Kocsis JD, Waxman SG (1997) Anoxic injury in the rat spinal cord: pharmacological evidence for multiple steps in Ca2+-dependent injury of the dorsal columns. J Neurotrauma 14:299–311

    Article  PubMed  CAS  Google Scholar 

  • Kapoor R (2008) Sodium channel blockers and neuroprotection in multiple sclerosis using lamotrigine. J Neurol Sci 274(1–2):54–56

    Article  PubMed  CAS  Google Scholar 

  • Kapoor R, Li R-G, Smith KJ (1997) Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons. Brain 120:647–652

    Article  PubMed  Google Scholar 

  • Kapoor R, Davies M, Smith KJ (1999) Temporary axonal conduction block and axonal loss in inflammatory neurological disease: a potential role for nitric oxide? Oxidative/Energy Metabolism in Neurodegenerative Disorders. Ann NY Acad Sci 893:304–308

    Article  PubMed  CAS  Google Scholar 

  • Kapoor R, Blaker PA, Hall SM, Davies M, Smith KJ (2000) Protection of axons from degeneration resulting from exposure to nitric oxide. Rev Neurol (Paris) 156:3S67

    Google Scholar 

  • 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 

  • Kaptanoglu E, Solaroglu I, Surucu HS, Akbiyik F, Beskonakli E (2005) Blockade of sodium channels by phenytoin protects ultrastructure and attenuates lipid peroxidation in experimental spinal cord injury. Acta Neurochi (Wien) 147:405–412

    Article  CAS  Google Scholar 

  • Khan N-A, 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 

  • Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267–276

    Article  PubMed  CAS  Google Scholar 

  • Korotzer AR, Cotman CW (1992) Voltage-gated currents expressed by rat microglia in culture. Glia 6:81–88

    Article  PubMed  CAS  Google Scholar 

  • Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212

    Article  PubMed  Google Scholar 

  • Lai Z-F, Chen Y-Z, 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 

  • 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 

  • LoPachin RM Jr, Stys PK (1995) Elemental composition and water content of rat optic nerve myelinated axons and glial cells: effects of in vitro anoxia and reoxygenation. J Neurosci 15(10):6735–6746

    PubMed  CAS  Google Scholar 

  • Lovas G, Szilagyi N, Majtenyi K, Palkovits M, Komoly S (2000) Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123:308–317

    Article  PubMed  Google Scholar 

  • Mahad D, Ziabreva I, Lassmann H, Turnbull D (2008) Mitochondrial defects in acute multiple sclerosis lesions. Brain 34:577–589

    CAS  Google Scholar 

  • 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 

  • Margaretten NC, Hincks JR, Warren RP, Coulombe RA Jr (1987) Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro. Toxicol Appl Pharmacol 87:10–17

    Article  PubMed  CAS  Google Scholar 

  • McDonald WI (1972) The time course of conduction failure during degeneration of a central tract. Exp Brain Res 14(5):550–556

    Article  PubMed  CAS  Google Scholar 

  • Narayanan S, Francis SJ, Sled JG, Santos AC, Antel S, Levesque I, Brass S, Lapierre Y, Sappey-Marinier D, Pike GB, Arnold DL (2006) Axonal injury in the cerebral normal-appearing white matter of patients with multiple sclerosis is related to concurrent demyelination in lesions but not to concurrent demyelination in normal-appearing white matter. Neuroimage 29:637–642

    Article  PubMed  Google Scholar 

  • Norenberg W, Illes P, Gebicke-Haerter PJ (1994) Sodium channels in isolated human brain macrophages (microglia). Glia 10:165–172

    Article  PubMed  CAS  Google Scholar 

  • Okada K, Sugiura T, Kuroda E, Tsuji S, Yamashita U (2001) Phenytoin promotes Th2 type immune response in mice. Clin Exp Immunol 124:406–413

    Article  PubMed  CAS  Google Scholar 

  • Okamoto Y, Shimizu K, Tamura K, Miyao Y, Yamada M, Tsuda N, Matsui Y, Mogami H (1988) Effects of phenytoin on cell-mediated immunity. Cancer Immunol Immunother 26:176–179

    Article  PubMed  CAS  Google Scholar 

  • Onuki M, Ayers MM, Bernard CC, Orian JM (2001) Axonal degeneration is an early pathological feature in autoimmune-mediated demyelination in mice. Microsc Res Tech 52(6):731–739

    Article  PubMed  CAS  Google Scholar 

  • Pöllmann W, Feneberg W (2008) Current management of pain associated with multiple sclerosis. CNS Drugs 22(4):291–324

    Article  PubMed  Google Scholar 

  • Raine CS, Cross AH (1989) Axonal dystrophy as a consequence of long-term demyelination. Lab Invest 60(5):714–725

    PubMed  CAS  Google Scholar 

  • Redford EJ, Kapoor R, Smith KJ (1997) Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 120:2149–2157

    Article  PubMed  Google Scholar 

  • Rogowski MA, Porter RJ (1990) Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 42:223–286

    Google Scholar 

  • Roselli F, Livrea P, Jirillo E (2006) Voltage-gated sodium channel blockers as immunomodulators. Rec Pat CNS Drug Discov 1:83–91

    Article  CAS  Google Scholar 

  • Rosenberg LJ, Teng YD, Wrathall JR (1999) Effects of the sodium channel blocker tetrodotoxin on acute white matter pathology after experimental contusive spinal cord injury. J Neurosci 19:6122–6133

    PubMed  CAS  Google Scholar 

  • Schmidtmayer J, Jacobsen C, Miksch G, Sievers J (1994) Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: membrane currents. Glia 12:259–267

    Article  PubMed  CAS  Google Scholar 

  • Schwartz G, Fehlings MG (2001) Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg 94(2 Suppl):245–256

    PubMed  CAS  Google Scholar 

  • Sedgwick JD, Schwender S, Imrich H (1991) Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci USA 88:7438–7442

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Soane L, Kahraman S, Kristian T, Fiskum G (2007) Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disorders. J Neurosci Res 85:3407–3415

    Article  PubMed  CAS  Google Scholar 

  • Steiner TJ, Silveira C, Yuan AWC, North Thames Lamictal Study Group (1994) Comparison of lamotrigine (Lamictal) and phenytoin in newly diagnosed epilepsy. Epilepsia 35:61

    Article  Google Scholar 

  • Steinman L, Zamvil SS (2006) How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60(1):12–21

    Article  PubMed  CAS  Google Scholar 

  • Stys PK, Waxman SG, Ransom BR (1991) Na+-Ca2+ exchanger mediates Ca2+ influx during anoxia in mammalian central nervous system white matter. Ann Neurol 30(3):375–380

    Article  PubMed  CAS  Google Scholar 

  • Stys PK, Ransom BR, Waxman SG (1992a) Tertiary and quaternary local anesthetics protect CNS white matter from anoxic injury at concentrations that do not block excitability. J Neurophysiol 67(1):236–240

    PubMed  CAS  Google Scholar 

  • Stys PK, Waxman SG, Ransom BR (1992b) 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 

  • Stys PK, Sontheimer H, Ransom BR, Waxman SG (1993) Non-inactivating TTX-sensitive Na+ conductance in rat optic nerves. Proc Natl Acad Sci USA 90:6976–6980

    Article  PubMed  CAS  Google Scholar 

  • Teng YD, Wrathall JR (1997) Local blockade of sodium channels by tetrodotoxin ameliorates ­tissue loss and long-term functional deficits resulting from experimental spinal cord injury. J Neurosci 17:4359–4366

    PubMed  CAS  Google Scholar 

  • Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285

    Article  PubMed  CAS  Google Scholar 

  • Waxman SG (2008) Sodium channels and neuroprotection in multiple sclerosis: current status. Nat Clin Pract Neurol 4(3):159–169

    Article  PubMed  CAS  Google Scholar 

  • Waxman SG, Black JA, Stys PK, Ransom BR (1992) Ultrastructural concomitants of anoxic injury and early post-anoxic recovery in rat optic nerve. Brain Res 574(1–2):105–119

    Article  PubMed  CAS  Google Scholar 

  • Waxman SG, Black JA, Ransom BR, Stys PK (1994) Anoxic injury of rat optic nerve: ultrastructural evidence for coupling between Na+ influx and Ca(2+)-mediated injury in myelinated CNS axons. Brain Res 644(2):197–204

    Article  PubMed  CAS  Google Scholar 

  • White SR, Black PC, Samathanam GK, Paros KC (1992) Prazosin suppresses development of axonal damage in rats inoculated for experimental allergic encephalomyelitis. J Neuroimmunol 39:211–218

    Article  PubMed  CAS  Google Scholar 

  • Wit AL, Rosen MR (1983) Pathophysiologic mechanisms of cardiac arrhythmias. Am Heart J 106(4 Pt 2):798–811

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Yamada M, Ohkawa M, Tamura K et al (2000) Anticonvulsant-induced suppression of IFN-Îł ­production by lymphocytes obtained from cervical lymph nodes in glioma-bearing mice. J Neurooncol 47:125–132

    Article  PubMed  CAS  Google Scholar 

  • Zamvil SS, Steinman L (1990) The T lymphocyte in experimental allergic encephalomyelitis. Ann Rev Immunol 8:579–621

    Article  CAS  Google Scholar 

  • Zamvil SS, Nelson PA, Mitchell DJ, Knobler RL, Fritz RB, Steinman L (1985) Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition. J Exp Med 162(6):2107–2124

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Research in the authors’ laboratories is supported by funds from the National Multiple Sclerosis Society (RG 1912), the Medical Research Service and Rehabilitation Research Service, Department of Veterans Affairs, the Brain Research Trust, the European Union (NeuroproMiSe), the Medical Research Council (UK), and the Multiple Sclerosis Society of G.B. and N.I.

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Authors and Affiliations

  1. Department of Neurology, Yale University School of Medicine, 20818, New Haven, CT, 06520, USA

    Joel A. Black & Stephen G. Waxman

  2. Paralyzed Veterans of America/United Spinal Association, Center for Neuroscience and Regeneration Research, Yale University School of Medicine, West Haven, CT, USA

    Joel A. Black & Stephen G. Waxman

  3. Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT, 06516, USA

    Joel A. Black & Stephen G. Waxman

  4. Department of Neuroinflammation, The Institute of Neurology (Queen Square), University College London, 1 Wakefield Street, London, WC1N 1PJ, UK

    Kenneth J. Smith

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  1. School Veterinary Medicine, Dept. Medical Sciences, University of Wisconsin Madison, Linden Drive West 2015, Madison, 53706-1102, Wisconsin, USA

    Ian D. Duncan

  2. Wellcome Trust and MRC Cambridge Stem Ce, and Department of Veterinary Medicine, University Cambridge, Madingley Road, Cambridge, CB3 0ES, United Kingdom

    Robin J M Franklin

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Black, J.A., Smith, K.J., Waxman, S.G. (2013). Axonal Protection with Sodium Channel Blocking Agents in Models of Multiple Sclerosis. In: Duncan, I., Franklin, R. (eds) Myelin Repair and Neuroprotection in Multiple Sclerosis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2218-1_8

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