Autoimmune encephalomyelitis ameliorated by AMPA antagonists.
Multiple sclerosis is an immune-mediated disorder of the central nervous system leading to progressive decline of motor and sensory functions and permanent disability. The therapy of multiple sclerosis is only partially effective, despite anti-inflammatory, immunosuppresive and immunomodulatory measures. White matter inflammation and loss of myelin, the pathological hallmarks of multiple sclerosis, are thought to determine disease severity. Experimental autoimmune encephalomyelitis reproduces the features of multiple sclerosis in rodents and in nonhuman primates. The dominant early clinical symptom of acute autoimmune encephalomyelitis is progressive ascending muscle weakness. However, demyelination may not be profound and its extent may not correlate with severity of neurological decline, indicating that targets unrelated to myelin or oligodendrocytes may contribute to the pathogenesis of acute autoimmune encephalomyelitis. Here we report that within the spinal cord in the course of autoimmune encephalomyelitis not only myelin but also neurons are subject to lymphocyte attack and may degenerate. Blockade of glutamate AMPA receptors ameliorated the neurological sequelae of autoimmune encephalomyelitis, indicating the potential for AMPA antagonists in the therapy of multiple sclerosis.
Smith
T
T
Eisai London Research Laboratories, Bernard Katz Building, University College London, Gower Street, London WC1E 6BT, UK.
Groom
A
A
Zhu
B
B
Turski
L
L
D000818:Animals; D001933:Brain Stem / Q000473:pathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006168:Guinea Pigs; D009046:Motor Neurons / Q000473:pathology; D009103:Multiple Sclerosis / Q000473:pathology / Q000628:therapy; D009129:Muscle Tonus; D004676:Myelin Basic Protein / Q000276:immunology; D009474:Neurons / Q000473:pathology*; D063065:Organophosphonates / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D012008:Recurrence; D013116:Spinal Cord / Q000473:pathology* / Q000648:ultrastructure; D013601:T-Lymphocytes / Q000473:pathology
D018691:Excitatory Amino Acid Antagonists; D004676:Myelin Basic Protein; D063065:Organophosphonates; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C114423:ZK 200775