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Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy
Author(s) -
Beraud Evelyne,
Viola Angèle,
Regaya Imed,
ConfortGouny Sylviane,
Siaud Philippe,
Ibarrola Danielle,
Le Fur Yann,
Barbaria Jocelyne,
Pellissier JeanFrançois,
Sabatier JeanMarc,
Medina Igor,
Cozzone Patrick J.
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21007
Subject(s) - remyelination , phosphocreatine , myelin , neuroscience , excitatory postsynaptic potential , chemistry , multiple sclerosis , medicine , endocrinology , blockade , experimental autoimmune encephalomyelitis , inhibitory postsynaptic potential , central nervous system , biology , immunology , receptor , energy metabolism
Objective We asked whether blockade of voltage‐gated K + channel Kv1.1, whose altered axonal localization during myelin insult and remyelination may disturb nerve conduction, treats experimental autoimmune encephalomyelitis (EAE). Methods Electrophysiological, cell proliferation, cytokine secretion, immunohistochemical, clinical, brain magnetic resonance imaging, and spectroscopy studies assessed the effects of a selective blocker of Kv1.1, BgK‐F6A, on neurons and immune cells in vitro and on EAE‐induced neurological deficits and brain lesions in Lewis rats. Results BgK‐F6A increased the frequency of miniature excitatory postsynaptic currents in neurons and did not affect T‐cell activation. EAE was characterized by ventriculomegaly, decreased apparent diffusion coefficient, and decreased (phosphocreatine + β‐adenosine triphosphate)/inorganic phosphate ratio. Reduced apparent diffusion coefficient and impaired energy metabolism indicate astrocytic edema. Intracerebroventricularly BgK‐F6A–treated rats showed attenuated clinical EAE with unexpectedly reduced ventriculomegaly and preserved apparent diffusion coefficient values and (phosphocreatine + β‐adenosine triphosphate)/inorganic phosphate ratio. Thus, under BgK‐F6A treatment, brain damage was dramatically reduced and energy metabolism maintained. Interpretation Kv1.1 blockade may target neurons and astrocytes, and modulate neuronal activity and neural cell volume, which may partly account for the attenuation of the neurological deficits. We propose that Kv1.1 blockade has a broad therapeutic potential in neuroinflammatory diseases (multiple sclerosis, stroke, and trauma). Ann Neurol 2006