title: Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis.
abstract: Axonal degeneration is a major cause of permanent disability in the inflammatory demyelinating disease multiple sclerosis, but no therapies are known to be effective in axonal protection. Sodium channel blocking agents can provide effective protection of axons in the white matter in experimental models of multiple sclerosis, but the mechanism of action (directly on axons or indirectly via immune modulation) remains uncertain. Here we have examined the efficacy of two sodium channel blocking agents to protect white matter axons in two forms of experimental autoimmune encephalomyelitis, a common model of multiple sclerosis. Safinamide is currently in phase III development for use in Parkinson's disease based on its inhibition of monoamine oxidase B, but the drug is also a potent state-dependent inhibitor of sodium channels. Safinamide provided significant protection against neurological deficit and axonal degeneration in experimental autoimmune encephalomyelitis, even when administration was delayed until after the onset of neurological deficit. Protection of axons was associated with a significant reduction in the activation of microglia/macrophages within the central nervous system. To clarify which property of safinamide was likely to be involved in the suppression of the innate immune cells, the action of safinamide on microglia/macrophages was compared with that of the classical sodium channel blocking agent, flecainide, which has no recognized monoamine oxidase B activity, and which has previously been shown to protect the white matter in experimental autoimmune encephalomyelitis. Flecainide was also potent in suppressing microglial activation in experimental autoimmune encephalomyelitis. To distinguish whether the suppression of microglia was an indirect consequence of the reduction in axonal damage, or possibly instrumental in the axonal protection, the action of safinamide was examined in separate experiments in vitro. In cultured primary rat microglial cells activated by lipopolysaccharide, safinamide potently suppressed microglial superoxide production and enhanced the production of the anti-oxidant glutathione. The findings show that safinamide is effective in protecting axons from degeneration in experimental autoimmune encephalomyelitis, and that this effect is likely to involve a direct effect on microglia that can result in a less activated phenotype. Together, this work highlights the potential of safinamide as an effective neuroprotective agent in multiple sclerosis, and implicates microglia in the protective mechanism.
authors.affiliation: Department of Neuroinflammation, UCL Institute of Neurology, Queen Square, 1 Wakefield Street, London, WC1N 1PJ, UK. damineh.morsali@gmail.com
authors.forename: Damineh
authors.initials: D
authors.lastname: Morsali
authors.forename: David
authors.initials: D
authors.lastname: Bechtold
authors.forename: Woojin
authors.initials: W
authors.lastname: Lee
authors.forename: Summen
authors.initials: S
authors.lastname: Chauhdry
authors.forename: Upayan
authors.initials: U
authors.lastname: Palchaudhuri
authors.forename: Paula
authors.initials: P
authors.lastname: Hassoon
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Snell
authors.forename: Katy
authors.initials: K
authors.lastname: Malpass
authors.forename: Thomas
authors.initials: T
authors.lastname: Piers
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pocock
authors.forename: Arthur
authors.initials: A
authors.lastname: Roach
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Smith
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D005424:Flecainide / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D026941:Sodium Channel Blockers / Q000627:therapeutic use
chemical_list: D001596:Benzylamines; D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; C092797:safinamide; D005424:Flecainide; D000409:Alanine