Treatment / Start of treatments post-immunization (days unless stated otherwise) / Mouse or rat strain / Outcome / Immune cell response/infiltration / Reference
AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors
NBQX / 5–15 / SJL/J mice / Reduction in clinical impairment; reduced neuroaxonal damage / No difference in comparison to vehicle / Pitt etal. (2000)1
NBQX / 10–17 / Lewis rats, Biozzi mice / Reduction in clinical impairment; reduced neuroaxonal damage / No difference in comparison to vehicle / Smith etal. (2000)2
MPQX / 10–17 / Lewis rats / Reduction in clinical impairment; reduced neuroaxonal damage / No difference in comparison to vehicle / Smith etal. (2000)2
NBQX / i) Day of clinical onset
ii) 60–74 / C57BL/6 mice / Reduction in clinical impairment / No difference in comparison to vehicle / Kanwar etal. (2004)3
NBQX / 5–12 / Lewis rats / Reduction in clinical impairment / Not tested / Ohgoh etal. (2002)4
NBQX / 10–20 / C57BL/6 mice / Reduction in clinical impairment; reduced dendritic spine loss / Not tested / Centonze etal. (2009)5
GYKI52466 / 10–17 / Lewis rats / Reduction in clinical impairment; reduced neuroaxonal damage / Not tested / Smith etal. (2000)2
GYKI53773 / 10–17 / Lewis rats / Reduction in clinical impairment; reduced neuroaxonal damage / Not tested / Smith etal. (2000)2
NMDA(N-methyl-d-aspartate) receptors
Memantine / 7–13 / Lewis rats / Reduction in clinical impairment / No difference in comparison to vehicle / Wallstrom etal. (1996)6
Memantine / i) 7–13
ii) 10–11 / Lewis rats / Reduction in clinical impairment / Reduction in inflammatory lesions / Paul & Bolton (2002)7
Memantine / 19–40 / NOD mice / Reduction in clinical impairment / Not tested / Basso etal. (2008)8
GPE / i) Day of clinical onset
ii) 60–74 / C57BL/6 mice / Reduction in clinical impairment / No difference in comparison to vehicle / Kanwar etal. (2004)3
Fullerene ABS-75 / i) 20–70
ii) 19–40 / NOD mice / Reduction in clinical impairment; reduced neuroaxonal damage (no difference reported in C57BL/6 or SJL/Jmice) / No difference in T-cell activation but reduced myeloid cell infiltration in the CNS in comparison to vehicle / Basso etal. (2008)8
Riluzole / i) 12–18
ii) 12–27
ii) 18–27 / C3H.SW mice / Reduction in clinical impairment; reduced neuroaxonal damage / No difference in T-cell activation but reduced immune cell infiltration in the CNS in comparison to vehicle / Gilgun-Sherki etal. (2003)9
MK-801 / 1 week before immunization (i.c.v.) / C57BL/6 mice / Reduction in clinical impairment; ameliorated synaptic transmission defects / Not tested, but continuousintracranial infusions by minipump implantation / Grasselli etal. (2013)10
Kv1.1 (voltage-gated K+ channel subtype 1.1)
BgK-F6A / Day 4 and 5 (i.c.v.) / Lewis rats / Reduced mortality; reduction in clinical impairment and brain damage / No change in peripheral T-cell activation;i.c.v. treatment by minipump or adoptive transfer EAE / Beraud etal. (2006)11
TASK1 (TWIK-related acid-sensitive potassium channel 1)
A293 / i) 0
ii) Day of clinical onset / C57BL/6 mice / Reduction in clinical impairment and demyelination / Reduced inflammatory infiltrate, T cell proliferation and cytokine production / Bittner etal. (2012)12
Nav (voltage-gated Na+ channels)
Carbamazepine / 10–28 / C57BL/6 mice / Reduction in clinical impairment; reduced neuroaxonal damage / Reduced inflammatory infiltrate / Black etal. (2007)13
Phenytoin / 10–30 / C57BL/6 mice / Reduction in clinical impairment; reduced neuroaxonal damage / Not tested / Lo etal. (2003)14
Phenytoin / 10–28 / C57BL/6 mice / Reduction in clinical impairment; reduced neuroaxonal damage / Reduced inflammatory infiltrate / Black etal. (2007)13
Phenytoin / i) 0–90
ii) 0–180
iii) 0–120 / C57BL/6 mice (i,ii); Biozzi mice (iii) / Ameliorated EAE course; reduced axonal loss / Reduced inflammatory cell infiltration / Black etal. (2006)15
Flecainide / 7–27 / Dark agouti rats / Reduction in clinical impairment / Reduced microglia/macrophage activation / Morsali etal. (2013)16
Flecainide / i) –3 to 27(30)
ii) 7–27(30) / Dark agouti rats / Reduction in clinical impairment; reduced neuroaxonal damage / Not tested / Bechtold etal. (2004)17
Lamotrigine / 7–27/29 / Dark agouti rats / Reduction in clinical impairment; reduced neuroaxonal damage / Not tested / Bechtold etal. (2006)18
A803467 / 10–15 (i.c.v.) / C57BL/6 mice / Significant partial reversal of symptoms 2–4h p.i. / Not tested / Shields etal. (2012)19
Safinamide / On reaching neurological deficit score of 2 for 16 days / Dark agouti rats / Reduction in clinical impairment; reduced neuroaxonal damage / Reduced area of demyelination and neurodegeneration; reduced microglia activation; reduced reactive oxygen speciesproduction by microglia / Morsali etal. (2013)16
L-type VGCC
Bepridil / i) 0–20
ii) 3–20 / SJL/J mice / Delayed disease onset andreduction in clinical impairment; reduced neuroaxonal damage; treatment started day 5 p.i. showed no significant impact on clinical disability / Reduced inflammatory infiltrate / Brand-Schieber etal. (2004)20
Nitrendipine / i) 0–20
ii) 3–20 / SJL/J mice / Delayed disease onset andreduction in clinical impairment; reduced neuroaxonal damage; treatment started day 5 p.i. showed no significant impact on clinical disability / Not tested / Brand-Schieber etal. (2004)20
N-type VGCC
ω-conotoxin GVIA / i) –2 to 21
ii) Day of clinical onset for 7 days / Brown Norway rats / Delayed disease onset andreduction in clinical impairment; reduced neuroaxonal damage in group i), but not in group ii) / Reduced inflammatory infiltrate in group i) / Gadjanski etal. (2009)21
ASIC1 (acid-sensing ion channel 1)
Amiloride / i) 5–30
ii) 15–50 / C57BL/6 mice / Reduction in clinical impairment; reduced neuroaxonal damage / No significant difference in immune cell infiltrate / Friese etal. (2007)22
Amiloride / i) Day of clinical onset
ii) First relapse / Biozzi ABH / Reduction in clinical impairment; reduced neuroaxonal damage; reduced demyelination / No significant difference in proportions or absolute cell numbers of T cells, B cells and macrophages. T-cell proliferation and cytokine production were not affected / Vergo etal. (2011)23
Transient receptor potential cation channel subfamily M member 4 (TRPM4)
Glibenclamide / Day of clinical onset / C57BL/6 mice / Reduction in clinical impairment; reduced axonal damage / No significant difference in immune cell infiltrate / Schattling etal. (2012)24
Colour code:
Green:proven neuroprotection—reduced neuronal and/or axonal damage without changes tothe immune response and CNS infiltration.
Red: neuroprotection,probablydue to reduced primary inflammatory response.
Grey: neuroprotection with inconclusive causal link owingto an absence of investigations into inflammatory response, or reduced myeloid inflammatory infiltrate, which could either be a response to the reduced CNS damage or bedirectly attributable to repressionby the treatment regime.
Abbreviations:A803467: 5-(4-chlorophenyl)-N-(3,5-dimethoxyphenyl)-2-furancarboxamide; EAE, experimental autoimmune encephalomyelitis;Fullerene ABS-75, C60 fullerene core attached to four adamantyl groups by oligoethyleneglycol bridges; GPE, glycine–proline–glutamic acid;GYK152466, 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine; GYK153773, 1-[(8R)-5-(4-aminophenyl)-8-methyl-8,9-dihydro-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]ethanone;i.c.v., intracerebroventricular; MPQX, [[3,4-dihydro-7-(4-morpholinyl)-2,3-dioxo-6-(trifluoromethyl)-1(2H)-quinoxalinyl]methyl]phosphonic acid; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide; p.i., post-injection; VGCC, voltage-gated Ca2+ channel.
1.Pitt, D., Werner, P. & Raine, C. S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med.6, 67–70 (2000).
2.Smith, T., Groom, A., Zhu, B. & Turski, L. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat. Med.6, 62–66 (2000).
3.Kanwar, J. R., Kanwar, R. K. & Krissansen, G. W. Simultaneous neuroprotection and blockade of inflammation reverses autoimmune encephalomyelitis. Brain 127, 1313–1331 (2004).
4.Ohgoh, M. et al. Altered expression of glutamate transporters in experimental autoimmune encephalomyelitis. J. Neuroimmunol.125, 170–178 (2002).
5.Centonze, D. et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J. Neurosci.29, 3442–3452 (2009).
6.Wallstrom, E. et al. Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. J. Neurol. Sci.137, 89–96 (1996).
7.Paul, C. & Bolton, C. Modulation of blood–brain barrier dysfunction and neurological deficits during acute experimental allergic encephalomyelitis by the N-methyl-d-aspartate receptor antagonist memantine. J. Pharmacol. Exp. Ther.302, 50–57 (2002).
8.Basso, A. S. et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J. Clin. Invest.118, 1532–1543 (2008).
9.Gilgun-Sherki, Y., Panet, H., Melamed, E. & Offen, D. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain Res.989, 196–204 (2003).
10.Grasselli, G. et al. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis. Br. J. Pharmacol.168, 502–517 (2013).
11.Beraud, E. et al. Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy. Ann. Neurol.60, 586–596 (2006).
12.Bittner, S. et al. The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis. Exp. Neurol.238, 149–155 (2012).
13.Black, J. A., Liu, S., Carrithers, M., Carrithers, L. M. & Waxman, S. G. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann. Neurol.62, 21–33 (2007).
14.Lo, A. C., Saab, C. Y., Black, J. A. & Waxman, S. G. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J. Neurophysiol.90, 3566–3571 (2003).
15.Black, J. A., Liu, S., Hains, B. C., Saab, C. Y. & Waxman, S. G. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain129, 3196–3208 (2006).
16.Morsali, D. et al. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain136, 1067–1082 (2013).
17.Bechtold, D. A., Kapoor, R. & Smith, K. J. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Ann. Neurol.55, 607–616 (2004).
18.Bechtold, D. A. et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J. Neurol.253, 1542–1551 (2006).
19.Shields, S. D. et al. A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis. Ann. Neurol.71, 186–194 (2012).
20.Brand-Schieber, E. & Werner, P. Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis. Exp. Neurol.189, 5–9 (2004).
21.Gadjanski, I. et al. Role of N-type voltage-dependent calcium channels in autoimmune optic neuritis. Ann. Neurol.66, 81–93 (2009).
22.Friese, M. A. et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat. Med.13, 1483–1489 (2007).
23.Vergo, S. et al. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain134, 571–584 (2011).
24.Schattling, B. et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med.18, 1805–1811 (2012).