Abstract:
OBJECTIVE:Cerebellar dysfunction in multiple sclerosis (MS) contributes significantly to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. We previously observed that sodium channel Nav1.8, whose expression is normally restricted to the peripheral nervous system, is present in cerebellar Purkinje neurons in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]) and in humans with MS. Here, we tested the hypothesis that upregulation of Nav1.8 in cerebellum in MS and EAE has functional consequences contributing to symptom burden. METHODS:Electrophysiology and behavioral assessment were performed in a new transgenic mouse model overexpressing Nav1.8 in Purkinje neurons. We also measured EAE symptom progression in mice lacking Nav1.8 compared to wild-type littermates. Finally, we administered the Nav1.8-selective blocker A803467 in the context of previously established EAE to determine reversibility of MS-like deficits. RESULTS:We report that, in the context of an otherwise healthy nervous system, ectopic expression of Nav1.8 in Purkinje neurons alters their electrophysiological properties, and disrupts coordinated motor behaviors. Additionally, we show that Nav1.8 expression contributes to symptom development in EAE. Finally, we demonstrate that abnormal patterns of Purkinje neuron firing and MS-like deficits in EAE can be partially reversed by pharmacotherapy using a Nav1.8-selective blocker. INTERPRETATION:Our results add to the evidence that a channelopathy contributes to cerebellar dysfunction in MS. Our data suggest that Nav1.8-specific blockers, when available for humans, merit study in MS.
journal_name
Ann Neuroljournal_title
Annals of neurologyauthors
Shields SD,Cheng X,Gasser A,Saab CY,Tyrrell L,Eastman EM,Iwata M,Zwinger PJ,Black JA,Dib-Hajj SD,Waxman SGdoi
10.1002/ana.22665subject
Has Abstractpub_date
2012-02-01 00:00:00pages
186-94issue
2eissn
0364-5134issn
1531-8249journal_volume
71pub_type
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410090507
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abstract::The blood-brain barrier is a natural diffusion barrier, which expresses active carriers extruding drugs on their way to the brain back into the blood against concentration gradients. Whereas these so-called adenosine triphosphate-binding cassette (ABC) transporters prevent the brain entry of toxic compounds under phys...
journal_title:Annals of neurology
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doi:10.1002/ana.21012
更新日期:2006-11-01 00:00:00
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abstract::Hyperekplexia is a rare, autosomal dominant neurological disorder characterized by hypertonia, especially in infancy, and by an exaggerated startle response. This disorder is caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). We previously reported two GLRA1 point mutations detected...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410380115
更新日期:1995-07-01 00:00:00
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journal_title:Annals of neurology
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journal_title:Annals of neurology
pub_type: 临床试验,杂志文章
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journal_title:Annals of neurology
pub_type: 杂志文章
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journal_title:Annals of neurology
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410270209
更新日期:1990-02-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
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journal_title:Annals of neurology
pub_type: 杂志文章,随机对照试验
doi:10.1002/ana.25561
更新日期:2019-10-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.20899
更新日期:2006-08-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410020407
更新日期:1977-10-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.22102
更新日期:2010-11-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.20141
更新日期:2004-07-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410200214
更新日期:1986-08-01 00:00:00
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journal_title:Annals of neurology
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doi:10.1002/ana.23664
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journal_title:Annals of neurology
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journal_title:Annals of neurology
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doi:10.1002/ana.24521
更新日期:2016-01-01 00:00:00
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doi:10.1002/ana.24362
更新日期:2015-05-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:
更新日期:2000-05-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.22222
更新日期:2011-05-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410080104
更新日期:1980-07-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:
更新日期:2000-04-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.25232
更新日期:2018-05-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.20175
更新日期:2004-08-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410260603
更新日期:1989-12-01 00:00:00
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journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.20110
更新日期:2004-05-01 00:00:00