Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.
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PMID:Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. 1102 57

Cerebellar deficits in multiple sclerosis (MS) tend to persist and can produce significant disability. Although the pathophysiological basis for these deficits is not clear, it was recently reported that the expression of the sensory neuron-specific sodium channel Nav1.8 (which is not normally expressed within the cerebellum) is aberrantly upregulated within Purkinje cells in experimental allergic encephalomyelitis (EAE) and in human MS. The expression of Nav1.8 in cultured Purkinje cells has been shown to alter the activity pattern of these cells in vitro by decreasing the number of spikes per conglomerate action potential and by contributing to the production of sustained, pacemaker-like activity upon depolarization, suggesting the hypothesis that, in pathophysiological situations where Nav1.8 is upregulated within Purkinje cells, the pattern of activity in these cells will be altered. In the present study, we examined this hypothesis in vivo in mice with EAE. Our results demonstrate a reduction in the number of secondary spikes per complex spike and irregularity in the temporal organization of secondary spikes in Purkinje cells from mice with EAE in which Nav1.8 is upregulated. We also observed abnormal bursting activity in Purkinje cells from mice with EAE, which was not observed in control animals. These results demonstrate functional changes in Purkinje cells in vivo within their native cerebellar environment in EAE, a model of MS, and support the hypothesis that misexpression of Nav1.8 can contribute to cerebellar deficits in neuroinflammatory disorders by altering the pattern of electrical activity within the cerebellum.
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PMID:Abnormal Purkinje cell activity in vivo in experimental allergic encephalomyelitis. 1511 96

Cerebellar symptoms significantly diminish quality of life in patients with multiple sclerosis (MS). We previously showed that sodium channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.8 expression is linked to ataxia and MS-like symptoms in mice. Furthermore, intracerebroventricular administration of the Nav1.8 blocker A-803467 temporarily reversed electrophysiological and behavioral manifestations of disease in a mouse MS model; unfortunately A-803467 is not orally bioavailable, diminishing the potential for translation to human patients. In the present study, we assessed the effect of per os (p.o.) dosing of a new orally bioavailable Nav1.8-selective blocker, PF-01247324, in transgenic mice expressing Nav1.8 in Purkinje neurons, and in wildtype mice in the experimental autoimmune encephalomyelitis (EAE) model. PF-01247324 was administered by oral gavage at 1000 mg/kg; control groups received an equal volume of vehicle. Behavioral assays of motor coordination, grip strength, and ataxia were performed. We observed significant improvements in motor coordination and cerebellar-like symptoms in mice that received PF-01247324 compared to control littermates that received vehicle. These preclinical proof-of-concept data suggest that PF-01247324, its derivatives, or other Nav1.8-selective blockers merit further study for providing symptomatic therapy for cerebellar dysfunction in MS and related disorders.
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PMID:Oral administration of PF-01247324, a subtype-selective Nav1.8 blocker, reverses cerebellar deficits in a mouse model of multiple sclerosis. 2574 79