TY - JOUR
T1 - 4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis
AU - Goebel, Kerstin
AU - Wedell, Jan-Hendrik
AU - Herrmann, Alexander M.
AU - Wachsmuth, Lydia
AU - Pankratz, Susann
AU - Bittner, Stefan
AU - Budde, Thomas
AU - Kleinschnitz, Christoph
AU - Faber, Cornelius
AU - Wiendl, Heinz
AU - Meuth, Sven G.
PY - 2013/10
Y1 - 2013/10
N2 - Neuropathological changes following demyelination in multiple sclerosis (MS) lead to a reorganization of axolemmal channels that causes conduction changes including conduction failure. Pharmacological modulation of voltage-sensitive potassium channels (K(V)) has been found to improve conduction in experimentally induced demyelination and produces symptomatic improvement in MS patients. Here we used an animal model of autoimmune inflammatory neurodegeneration, namely experimental autoimmune encephalomyelitis (EAE), to test the influence of the K(V)-inhibitor 4-aminopyridine (4-AP) on various disease and immune parameters as well as mobility in MOG? immunized C57Bl/6 mice. We challenged the hypothesis that 4-AP exerts relevant immunomodulatory or neuroprotective properties. Neither prophylactic nor therapeutic treatment with 4-AP altered disease incidence or disease course of EAE. Histopathological signs of demyelination and neuronal damage as well as MRI imaging of brain volume changes were unaltered. While application of 4-AP significantly reduced the standing outward current of stimulated CD4(+) T cells compared to controls, it failed to impact intracellular calcium concentrations in these cells. Compatibly, KV channel inhibition neither influenced CD4(+) T cell effector functions (proliferation, IL17 or IFN? production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, 1) foot print and 2) rotarod analysis (0.332 ? 0.03, n=7 versus 0.399 ? 0.08, n=14, p
AB - Neuropathological changes following demyelination in multiple sclerosis (MS) lead to a reorganization of axolemmal channels that causes conduction changes including conduction failure. Pharmacological modulation of voltage-sensitive potassium channels (K(V)) has been found to improve conduction in experimentally induced demyelination and produces symptomatic improvement in MS patients. Here we used an animal model of autoimmune inflammatory neurodegeneration, namely experimental autoimmune encephalomyelitis (EAE), to test the influence of the K(V)-inhibitor 4-aminopyridine (4-AP) on various disease and immune parameters as well as mobility in MOG? immunized C57Bl/6 mice. We challenged the hypothesis that 4-AP exerts relevant immunomodulatory or neuroprotective properties. Neither prophylactic nor therapeutic treatment with 4-AP altered disease incidence or disease course of EAE. Histopathological signs of demyelination and neuronal damage as well as MRI imaging of brain volume changes were unaltered. While application of 4-AP significantly reduced the standing outward current of stimulated CD4(+) T cells compared to controls, it failed to impact intracellular calcium concentrations in these cells. Compatibly, KV channel inhibition neither influenced CD4(+) T cell effector functions (proliferation, IL17 or IFN? production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, 1) foot print and 2) rotarod analysis (0.332 ? 0.03, n=7 versus 0.399 ? 0.08, n=14, p
KW - 4-Aminopyridine
KW - Multiple sclerosis
KW - EAE
KW - Symptomatic treatment
KW - Mobility
U2 - 10.1016/j.expneurol.2013.05.016
DO - 10.1016/j.expneurol.2013.05.016
M3 - Article
C2 - 23748135
SN - 0014-4886
VL - 248
SP - 62
EP - 71
JO - Experimental Neurology
JF - Experimental Neurology
ER -