Oral administration of PF-01247324, a subtype-selective Nav1.8 blocker, reverses cerebellar deficits in a mouse model of multiple sclerosis.
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.
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, United States of America; Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
Shannon D
SD
Shields
Neusentis UK, Pfizer Global R&D, Cambridge, United Kingdom.
Richard P
RP
Butt
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, United States of America; Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
Sulayman D
SD
Dib-Hajj
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, United States of America; Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
Stephen G
SG
Waxman
D000284:Administration, Oral; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; D061567:Voltage-Gated Sodium Channel Blockers