Multiple sclerosis and glutamate.
Experimental autoimmune encephalomyelitis reproduces in rodents the features of multiple sclerosis, an immune-mediated, disabling disorder of the human nervous system. No adequate therapy is available for multiple sclerosis, despite anti-inflammatory, immunosuppressive, and immunomodulatory measures. Increasingly glutamate is implicated in the pathogenesis of neurodegenerative diseases. Here we (1) review changes in the glutamatergic system in multiple sclerosis and (2) reveal the effects of glutamate AMPA antagonists in acute and chronic rodent models of multiple sclerosis. Administration of structurally diverse competitive and non-competitive AMPA antagonists reduces neurologic disability in rodents subjected to acute experimental autoimmune encephalomyelitis. In addition, AMPA antagonists are active in both the adoptive transfer and in chronic models of experimental autoimmune encephalomyelitis in rats and mice and affect both the acute and chronic relapsing phases. Moreover, short-term therapy with AMPA antagonists leads to sustained benefit well into the progressive phases. These results imply that therapeutic strategies for multiple sclerosis should be complemented by glutamate AMPA antagonists to reduce neurologic disability.
Groom
Anthony J
AJ
Eisai London Research Laboratories, University College London, Bernard Katz Building, Gower Street, United Kingdom.
Smith
Terence
T
Turski
Lechoslaw
L
D000818:Animals; D001933:Brain Stem / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use; D011810:Quinoxalines / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure
D018691:Excitatory Amino Acid Antagonists; D018697:Nootropic Agents; D011760:Pyrrolidinones; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; C036466:aniracetam