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

Abstract

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 (MOG(35-55)) 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.

• Authors: Stefan Bittner, Marcella A Bauer, Petra Ehling, Nicole Bobak, Johanna Breuer, Alexander M Herrmann, Melina Golfels, Heinz Wiendl, Thomas Budde, Sven G Meuth
• Journal: Experimental neurology (Exp Neurol) Vol. 238 Issue 2 Pg. 149-55 (Dec 2012) ISSN: 1090-2430 [Electronic] United States
• PMID: 22960185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• 2-(butane-1-sulfonylamino)-N-(1-(6-methoxypyridin-3-yl)propyl)benzamide
• CD11b Antigen
• Cytokines
• Myelin-Oligodendrocyte Glycoprotein
• Nerve Tissue Proteins
• Peptide Fragments
• Potassium Channel Blockers
• Potassium Channels
• Potassium Channels, Tandem Pore Domain
• Sulfonamides
• TASK3 protein, mouse
• myelin oligodendrocyte glycoprotein (34-56)
• ortho-Aminobenzoates
• potassium channel subfamily K member 3

Topics

• Animals
• 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
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, etiology, genetics, pathology)
• Flow Cytometry
• Membrane Potentials (drug effects, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myelin-Oligodendrocyte Glycoprotein (toxicity)
• Nerve Tissue Proteins (antagonists & inhibitors, deficiency)
• Peptide Fragments (toxicity)
• Potassium Channel Blockers (chemistry, therapeutic use)
• Potassium Channels (deficiency)
• Potassium Channels, Tandem Pore Domain (antagonists & inhibitors, deficiency)
• Sulfonamides (pharmacology, therapeutic use)
• Time Factors
• ortho-Aminobenzoates (pharmacology, therapeutic use)