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: Sarah Al-Izki, Gareth Pryce, Deborah J R Hankey, Katie Lidster, Stephanie M von Kutzleben, Lorcan Browne, Lisa Clutterbuck, Cristina Posada, A W Edith Chan, Sandra Amor, Victoria Perkins, Wouter H Gerritsen, Kim Ummenthum, Regina Peferoen-Baert, Paul van der Valk, Alexander Montoya, Simon P Joel, John Garthwaite, Gavin Giovannoni, David L Selwood, David Baker
• Journal: Brain : a journal of neurology (Brain) Vol. 137 Issue Pt 1 Pg. 92-108 (Jan 2014) ISSN: 1460-2156 [Electronic] England
• PMID: 24287115 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Benzamides
• CFM6104
• Carrier Proteins
• Indazoles
• Neuroprotective Agents
• Oxadiazoles
• Sodium Channel Blockers
• Voltage-Gated Sodium Channels
• Carbamazepine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Benzamides (therapeutic use)
• Biological Specimen Banks
• Brain (pathology)
• Carbamazepine (pharmacology)
• Carrier Proteins (metabolism)
• Cell Proliferation (drug effects)
• Chromatography, High Pressure Liquid
• Drug Delivery Systems
• Encephalomyelitis, Autoimmune, Experimental (metabolism)
• Female
• Immunohistochemistry
• Indazoles (therapeutic use)
• Mass Spectrometry
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis (drug therapy, physiopathology)
• Neuroprotective Agents (therapeutic use)
• Optic Neuritis (physiopathology)
• Oxadiazoles (therapeutic use)
• Sodium Channel Blockers (therapeutic use)
• T-Lymphocytes (drug effects)
• Uveitis (physiopathology)
• Voltage-Gated Sodium Channels (metabolism)