The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis

The two-pore domain potassium channel TASK1 (KCNK3) has recently emerged as an important modulator in autoimmune CNS inflammation. Previously, it was shown that T lymphocytes obtained from TASK1−/− mice display impaired T cell effector functions and that TASK1−/− mice show a significantly reduced di...

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Bibliographic Details
Published in:Experimental neurology 2012-12, Vol.238 (2), p.149-155
Main Authors: Bittner, Stefan, Bauer, Marcella A., Ehling, Petra, Bobak, Nicole, Breuer, Johanna, Herrmann, Alexander M., Golfels, Melina, Wiendl, Heinz, Budde, Thomas, Meuth, Sven G.
Format: Article
Language:English
Subjects:
A293
Animals
Biological and medical sciences
CD11b Antigen - metabolism
CD4-Positive T-Lymphocytes - drug effects
CD8-Positive T-Lymphocytes - drug effects
Cell Proliferation - drug effects
Cytokines - metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
EAE
Encephalomyelitis, Autoimmune, Experimental - drug therapy
Encephalomyelitis, Autoimmune, Experimental - etiology
Encephalomyelitis, Autoimmune, Experimental - genetics
Encephalomyelitis, Autoimmune, Experimental - pathology
Experimental autoimmune encephalomyelitis
Flow Cytometry
Ion channel blocker
K2P channels
Medical sciences
Membrane Potentials - drug effects
Membrane Potentials - genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiple sclerosis
Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis
Myelin-Oligodendrocyte Glycoprotein - toxicity
Nerve Tissue Proteins - antagonists & inhibitors
Nerve Tissue Proteins - deficiency
Neurology
ortho-Aminobenzoates - pharmacology
ortho-Aminobenzoates - therapeutic use
Peptide Fragments - toxicity
Potassium Channel Blockers - chemistry
Potassium Channel Blockers - therapeutic use
Potassium channels
Potassium Channels - deficiency
Potassium Channels, Tandem Pore Domain - antagonists & inhibitors
Potassium Channels, Tandem Pore Domain - deficiency
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
TASK1
Time Factors
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Summary:The two-pore domain potassium channel TASK1 (KCNK3) has recently emerged as an important modulator in autoimmune CNS inflammation. Previously, it was shown that T lymphocytes obtained from TASK1−/− mice display impaired T cell effector functions and that TASK1−/− mice show a significantly reduced disease severity in myelin oligodendrocyte glycoprotein (MOG35–55) peptide induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We here evaluate a potent and specific TASK1 channel inhibitor, A293, which caused a dose-dependent reduction of T cell effector functions (cytokine production and proliferation). This effect was abolished in CD4+ T cells from TASK1−/− mice but not in cells from TASK3−/− mice. In electrophysiological measurements, A293 application induced a significant reduction of the outward current of wildtype T lymphocytes, while there was no effect in TASK1−/− cells. Preventive and therapeutic application of A293 significantly ameliorated the EAE disease course in wildtype mice while it had no significant effect in TASK1−/− mice and was still partly effective in TASK3−/− mice. In summary, our findings support the concept of TASK1 as an attractive drug target for autoimmune disorders. ► A293, a selective TASK1 inhibitor, leads to a reduction of T cell effector functions. ► Application of A293 ameliorates the disease course in the MOG-induced EAE model. ► These effects were abolished in TASK1 knockout mice.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2012.08.021