Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Multiple Sclerosis | Research

Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis

Authors: Barakat Alrashdi, Bassel Dawod, Andrea Schampel, Sabine Tacke, Stefanie Kuerten, Jean S. Marshall, Patrice D. Côté

Published in: Journal of Neuroinflammation | Issue 1/2019

Login to get access

Abstract

Background

In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca2+ ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking.

Methods

In mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control.

Results

In retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health.

Conclusion

Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.
Appendix
Available only for authorised users
Literature
1.
Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev. 2010;9:A387–94.PubMedCrossRef
2.
Mohr DC. Psychiatric Disorders, Stress, and Their Treatment Among People with Multiple Sclerosis. Psychol Co-morbidities Phys Illn. 2011:311–34.
3.
Constantinescu CS, Farooqi N, O’Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164:1079–106.PubMedPubMedCentralCrossRef
4.
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278–85.PubMedCrossRef
5.
de Leeuw CN, Dyka FM, Boye SL, Laprise S, Zhou M, Chou AY, et al. Targeted CNS delivery using human MiniPromoters and demonstrated compatibility with adeno-associated viral vectors. Mol Ther Methods Clin Dev. 2014;1:5.PubMedPubMedCentralCrossRef
6.
Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci. 2003;206:165–71.PubMedCrossRef
7.
Mancardi G, Hart B, Roccatagliata L, Brok H, Giunti D, Bontrop R, et al. Demyelination and axonal damage in a non-human primate model of multiple sclerosis. J Neurol Sci. 2001;184:41–9.PubMedCrossRef
8.
Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol. 2014;10:225–38.PubMedCrossRef
9.
Krzemien DM, Schaller KL, Levinson SR, Caldwell JH. Immunolocalization of sodium channel isoform NaCh6 in the nervous system. J Comp Neurol. 2000;420:70–83.PubMedCrossRef
10.
Craner MJ. Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain. 2003;126:1552–61.PubMedCrossRef
11.
Craner MJ, Hains BC, Lo AC, Black JA, Waxman SG. Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain. 2004;127:294–303.PubMedCrossRef
12.
Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. 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. 2004;101:8168–73.PubMedCrossRefPubMedCentral
13.
Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain. 1997;120:393–9.PubMedCrossRef
14.
15.
Levin SI, Meisler MH. Floxed allele for conditional inactivation of the voltage-gated sodium channel Scn8a (Nav1.6). Genesis. 2004;39:234–9.PubMedCrossRef
16.
Kuerten S, Kostova-Bales DA, Frenzel LP, Tigno JT, Tary-Lehmann M, Angelov DN, et al. MP4- and MOG:35-55-induced EAE in C57BL/6 mice differentially targets brain, spinal cord and cerebellum. J Neuroimmunol. 2007;189:31–40.PubMedPubMedCentralCrossRef
17.
Miller SD, Karpus WJ, Davidson TS. Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol. 2010;88:15–1.
18.
Smith CA, Chauhan BC. Imaging retinal ganglion cells: enabling experimental technology for clinical application. Prog Retin Eye Res. 2015;44:1–14.PubMedCrossRef
19.
Rodriguez AR, de Sevilla Müller LP, Brecha NC. The RNA binding protein RBPMS is a selective marker of ganglion cells in the mammalian retina. J Comp Neurol. 2014;522:1411–43.PubMedPubMedCentralCrossRef
20.
Kuerten S, Gruppe TL, Laurentius LM, Kirch C, Tary-Lehmann M, Lehmann PV, et al. Differential patterns of spinal cord pathology induced by MP4, MOG peptide 35-55, and PLP peptide 178-191 in C57BL/6 mice. Apmis. 2011;119:336–46.PubMedCrossRef
21.
Guy J, Ellis EA, Hope GM, Emerson S. Maintenance of myelinated fibre g ratio in acute experimental allergic encephalomyelitis. Brain. 1991;114A:281–94.
22.
Waxman SG. Axonal conduction and injury in multiple sclerosis: The role of sodium channels. Nat Rev Neurosci. 2006;7:932–41.PubMedCrossRef
23.
Kwong JMK, Caprioli J, Piri N. RNA binding protein with multiple splicing: a new marker for retinal ganglion cells. Investig Ophthalmol Vis Sci. 2010;51:1052–8.CrossRef
24.
Giuliodori MJ, DiCarlo SE. Myelinated Vs. unmyelinated nerve conduction: a novel way of understanding the mechanisms. Adv Physiol Educ. 2004;28:80–1.PubMedCrossRef
25.
Buffington SA, Rasband MN. Structure and Function of Myelinated Axons. Compr Dev Neurosci Patterning Cell Type Specif Dev CNS PNS; 2013. p. 707–22.
26.
Foster RE, Whalen CC, Waxman SG. Reorganization of the axon membrane in demyelinated peripheral nerve fibers: morphological evidence. Science. 1980;210:661–3.PubMedCrossRef
27.
Novakovic SD, Levinson SR, Schachner M, Shrager P. Disruption and reorganization of sodium channels in experimental allergic neuritis. Muscle Nerve. 1998;21:1019–32.PubMedCrossRef
28.
England JD, Gamboni F, Levinson SR. Increased numbers of sodium channels form along demyelinated axons. Brain Res. 1991;548:334–7.PubMedCrossRef
29.
Moll C, Mourre C, Lazdunski M, Ulrich J. Increase of sodium channels in demyelinated lesions of multiple sclerosis. Brain Res. 1991;556:311–6.PubMedCrossRef
30.
Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. J Neurosci. 1992;12:430–9 0.PubMedPubMedCentralCrossRef
31.
Bouafia A, Golmard JL, Thuries V, Sazdovitch V, Hauw JJ, Fontaine B, et al. Axonal expression of sodium channels and neuropathology of the plaques in multiple sclerosis. Neuropathol Appl Neurobiol. 2014;40:579–90.PubMedCrossRef
32.
33.
Kohrman DC, Smith MR, Goldin AL, Harris J, Meisler MH. A missense mutation in the sodium channel Scn8a is responsible for cerebellar ataxia in the mouse mutant jolting. J Neurosci. 1996;16:5993–9.PubMedPubMedCentralCrossRef
34.
Burgess DL, Kohrman DC, Galt J, Plummer NW, Jones JM, Spear B, et al. Mutation of a new sodium channel gene, Scn8a, in the mouse mutant ‘motor endplate disease.’. Nat Genet. 1995;10:461–5.PubMedCrossRef
35.
36.
Soares RMG, Dias AT, De Castro SBR, Alves CCS, Evangelista MG, Da Silva LC, et al. Optical neuritis induced by different concentrations of myelin oligodendrocyte glycoprotein presents different profiles of the inflammatory process. Autoimmunity. 2013;46:480–5.PubMedCrossRef
37.
Smith CA, Chauhan BC. In vivo imaging of adeno-associated viral vector labelled retinal ganglion cells. Sci Rep. 2018;8.
38.
Stromnes IM, Goverman JM. Passive induction of experimental allergic encephalomyelitis. Nat Protoc. 2006;1:1952–60.PubMedCrossRef
39.
Shindler KS, Ventura E, Dutt M, Rostami A. Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis. Exp Eye Res. 2008;87:208–13.PubMedPubMedCentralCrossRef
40.
Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 2012;33:579–89.PubMedCrossRef
41.
Barnett MH, Henderson APD, Prineas JW. The macrophage in MS: Just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Mult Scler. 2006;12:121–32.PubMedCrossRef
42.
Wojkowska DW, Szpakowski P, Ksiazek-Winiarek D, Leszczynski M, Glabinski A. Interactions between neutrophils, Th17 cells, and chemokines during the initiation of experimental model of multiple sclerosis. Mediat Inflamm. 2014;2014:1–8.CrossRef
43.
Duffy SS, Lees JG, Moalem-Taylor G. The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult Scler Int. 2014;2014:1–17.CrossRef
44.
Serada S, Fujimoto M, Mihara M, Koike N, Ohsugi Y, Nomura S, et al. IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci. 2008;105:9041–6.PubMedCrossRefPubMedCentral
45.
Matsuki T, Nakae S, Sudo K, Horai R, Iwakura Y. Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int Immunol. 2006;18:399–407.PubMedCrossRef
46.
Lin C-C, Edelson BT. New insights into the role of IL-1β in experimental autoimmune encephalomyelitis and multiple sclerosis. J Immunol. 2017;198:4553–60.PubMedCrossRef
47.
Horstmann L, Schmid H, Heinen AP, Kurschus FC, Dick HB, Joachim SC. Inflammatory demyelination induces glia alterations and ganglion cell loss in the retina of an experimental autoimmune encephalomyelitis model. J Neuroinflammation. 2013;10.
48.
Wilmes AT, Reinehr S, Kühn S, Pedreiturria X, Petrikowski L, Faissner S, et al. Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model. J Neuroinflammation. 2018;15.
49.
Eijkelkamp N, Linley JE, Baker MD, Minett MS, Cregg R, Werdehausen R, et al. Neurological perspectives on voltage-gated sodium channels. Brain. 2012;135:2585–612.PubMedPubMedCentralCrossRef
50.
Carrithers MD, Chatterjee G, Carrithers LM, Offoha R, Iheagwara U, Rahner C, et al. Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A. J Biol Chem. 2009;284:8114–26.PubMedPubMedCentralCrossRef
51.
Craner MJ, Damarjian TG, Liu S, Hains BC, Lo AC, Black JA, et al. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia. 2005;49:220–9.PubMedCrossRef
52.
Black JA, Liu S, Waxman SG. Sodium channel activity modulates multiple functions in microglia. Glia. 2009;57:1072–81.PubMedCrossRef
53.
54.
Hellström M, Ruitenberg MJ, Pollett MA, Ehlert EME, Twisk J, Verhaagen J, et al. Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection. Gene Ther. 2009;16:521–32.PubMedCrossRef
55.
Kolbe S, Chapman C, Nguyen T, Bajraszewski C, Johnston L, Kean M, et al. Optic nerve diffusion changes and atrophy jointly predict visual dysfunction after optic neuritis. Neuroimage. 2009;45:679–86.PubMedCrossRef
56.
Horstmann L, Kuehn S, Pedreiturria X, Haak K, Pfarrer C, Dick HB, et al. Microglia response in retina and optic nerve in chronic experimental autoimmune encephalomyelitis. J Neuroimmunol. 2016;298:32–41.PubMedCrossRef
57.
O’Malley HA, Shreiner AB, Chen GH, Huffnagle GB, Isom LL. Loss of Na+ channel β2 subunits is neuroprotective in a mouse model of multiple sclerosis. Mol Cell Neurosci. 2009;40:143–55.PubMedCrossRef
58.
Stys PK, Waxman SG, Ransom BR. Na+−Ca2+ exchanger mediates Ca2+ influx during anoxia in mammalian central nervous system white matter. Ann Neurol. 1991;30:375–80.PubMedCrossRef
59.
Kapoor R, Davies M, Blaker PA, Hall SM, Smith KJ. Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol. 2003;53:174–80.PubMedCrossRef
60.
Garthwaite G, Goodwin DA, Batchelor AM, Leeming K, Garthwaite J. Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience. 2002;109:145–55.PubMedCrossRef
61.
Bechtold DA, Kapoor R, Smith KJ. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann Neurol. 2004;55:607–16.PubMedCrossRef
62.
Morsali D, Bechtold D, Lee W, Chauhdry S, Palchaudhuri U, Hassoon P, et al. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain. 2013;136:1067–82.PubMedCrossRef
63.
Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010;9:681–8.PubMedCrossRef
64.
Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-Current status. Nat Clin Pract Neurol. 2008;4:159–69.PubMedCrossRef
65.
Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:259–69.PubMedCrossRef
66.
Yang C, Hao Z, Zhang L, Zeng L, Wen J. Sodium channel blockers for neuroprotection in multiple sclerosis. Cochrane Database of Systematic Reviews. 2015, Issue 10. Art. No.: CD010422.
67.
Rosker C, Lohberger B, Hofer D, Steinecker B, Quasthoff S, Schreibmayer W. The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Na v1.6 voltage-dependent sodium channel. Am J Physiol Physiol. 2007;293:C783–9.CrossRef
68.
Teramoto N, Yotsu-Yamashita M. Selective blocking effects of 4,9-anhydrotetrodotoxin, purified from a crude mixture of tetrodotoxin analogues, on NaV1.6 channels and its chemical aspects. Mar Drugs. 2015;13:984–95.PubMedPubMedCentralCrossRef
69.
Hargus NJ, Nigam A, Bertram EH, Patel MK. Evidence for a role of Na v 1.6 in facilitating increases in neuronal hyperexcitability during epileptogenesis. J Neurophysiol. 2013;110:1144–57.PubMedPubMedCentralCrossRef
70.
Li L, Shao J, Wang J, Liu Y, Zhang Y, Zhang M, et al. MiR-30b-5p attenuates oxaliplatin-induced peripheral neuropathic pain through the voltage-gated sodium channel Na v 1.6 in rats. Neuropharmacology. 2019;153:111–20.PubMedCrossRef
71.
Meisler MH, Kearney J, Escayg A, MacDonald BT, Sprunger LK. Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. Neuroscientist. 2001;7:136–45.PubMedCrossRef
72.
Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron. 2001;30:91–104.PubMedCrossRef
73.
Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, Barres BA. Differential control of clustering of the sodium channels Nav1.2 and Nav1.6 at developing CNS nodes of Ranvier. Neuron. 2001;30:105–19.PubMedCrossRef
74.
Metadata
Title
Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis
Authors
Barakat Alrashdi
Bassel Dawod
Andrea Schampel
Sabine Tacke
Stefanie Kuerten
Jean S. Marshall
Patrice D. Côté
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1622-1

Other articles of this Issue 1/2019

Journal of Neuroinflammation 1/2019 Go to the issue

Research

Deficiency of TREK-1 potassium channel exacerbates blood-brain barrier damage and neuroinflammation after intracerebral hemorrhage in mice

Correction

Correction to: The atypical RhoGTPase RhoE/Rnd3 is a key molecule to acquire a neuroprotective phenotype in microglia

Research

The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression

Research

The retinal environment induces microglia-like properties in recruited myeloid cells

Research

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Research

Cytokine inflammatory threat, but not LPS one, shortens GABAergic synaptic currents in the mouse spinal cord organotypic cultures