title: Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.
abstract: Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal sodium channels can trigger axonal degeneration, recent studies have tested sodium channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, sodium channel blockers may also interfere with inflammatory mechanisms. We therefore examined the novel hypothesis that sodium channels contribute to activation of microglia and macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of sodium channel Nav1.6 expression in activated microglia and macrophages in EAE and MS. We further demonstrate that treatment with the sodium channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%. Supporting a role for sodium channels in microglial activation, we show that tetrodotoxin, a specific sodium channel blocker, reduces the phagocytic function of activated rat microglia by 40%. To further confirm a role of Nav1.6 in microglial activation, we examined the phagocytic capacity of microglia from med mice, which lack Nav1.6 channels, and show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice. Our findings indicate that sodium channels are important for activation and phagocytosis of microglia and macrophages in EAE and MS and suggest that, in addition to a direct neuroprotective effect on axons, sodium channel blockade may ameliorate neuroinflammatory disorders via anti-inflammatory mechanisms.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, Connecticut 06520-8018, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Craner
authors.forename: Tina G
authors.initials: TG
authors.lastname: Damarjian
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Hains
authors.forename: Albert C
authors.initials: AC
authors.lastname: Lo
authors.forename: Joel A
authors.initials: JA
authors.lastname: Black
authors.forename: Jia
authors.initials: J
authors.lastname: Newcombe
authors.forename: M Louise
authors.initials: ML
authors.lastname: Cuzner
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C491046:Scn8a protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D010672:Phenytoin