title: Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis.
abstract: Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.
authors.affiliation: 1 Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Al-Izki
authors.forename: Gareth
authors.initials: G
authors.lastname: Pryce
authors.forename: Deborah J R
authors.initials: DJ
authors.lastname: Hankey
authors.forename: Katie
authors.initials: K
authors.lastname: Lidster
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: von Kutzleben
authors.forename: Lorcan
authors.initials: L
authors.lastname: Browne
authors.forename: Lisa
authors.initials: L
authors.lastname: Clutterbuck
authors.forename: Cristina
authors.initials: C
authors.lastname: Posada
authors.forename: A W
authors.initials: AW
authors.lastname: Edith Chan
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
authors.forename: Victoria
authors.initials: V
authors.lastname: Perkins
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.forename: Kim
authors.initials: K
authors.lastname: Ummenthum
authors.forename: Regina
authors.initials: R
authors.lastname: Peferoen-Baert
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Alexander
authors.initials: A
authors.lastname: Montoya
authors.forename: Simon P
authors.initials: SP
authors.lastname: Joel
authors.forename: John
authors.initials: J
authors.lastname: Garthwaite
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: David L
authors.initials: DL
authors.lastname: Selwood
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D018070:Biological Specimen Banks; D001921:Brain / Q000473:pathology; D002220:Carbamazepine / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007191:Indazoles / Q000627:therapeutic use*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009902:Optic Neuritis / Q000503:physiopathology; D010069:Oxadiazoles / Q000627:therapeutic use*; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects; D014605:Uveitis / Q000503:physiopathology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; C586919:CFM6104; D002352:Carrier Proteins; D007191:Indazoles; D018696:Neuroprotective Agents; D010069:Oxadiazoles; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D002220:Carbamazepine
keywords: animal models; experimental allergic encephalomyelitis; multiple sclerosis; neural repair