Symptomatic treatment effect of sodium channel blockers

Sodium channel blockers may be able to improve unsteadiness of gait in MSers. #MSBlog #MSResearch

"Nerves use sodium channels to conduct electrical signals. By allowing sodium to flow into the cell via sodium channels in a sequential fashion allows the cell membrane to conduct a electrical signal down an axon or nerve process. There are many different types of sodium channels. Some sodium channels open spontaneously and leak sodium; this affects the functioning of nerve cells. In MS certain neurons that are damaged by demyelination express different sodium channels; we call this aberrant expression. If these aberrant sodium channels leak sodium is causes that nerve cell to malfunction. This is what happens in the cerebellum or mini-brain that controls balance in MSers."
"In the study below the researchers show that blocking aberrant sodium channels (Nav1.8) with a new drug improves the functioning of the cerebellum. They use two different animal models; one that is engineered to express aberrant sodium channels and the other an animal model of MS called EAE. This is an exciting paper as it shows another potential use of sodium channel blockers in MS. We are currently exploring two different sodium channel blockers as neuroprotective therapies in MS. One study is looking at phenytoin in acute optic neuritis and the other oxcarbazepine as an add-on therapy in MSers with early SPMS (PROXIMUS TRIAL)."

Shields et al. Oral Administration of PF-01247324, a Subtype-Selective Nav1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis. PLoS One. 2015 Mar 6;10(3):e0119067. doi: 10.1371/journal.pone.0119067. eCollection 2015.

Background: Cerebellar symptoms significantly diminish quality of life in MSers. 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 (unsteadiness of gait) 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. 


Objective: 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. 

Methods: 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. 

Results: We observed significant improvements in motor coordination and cerebellar-like symptoms in mice that received PF-01247324 compared to control littermates that received vehicle. 

Conclusion: 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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