The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood-brain barrier disruption: implications for multiple sclerosis treatment.
Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is a widely used animal model for multiple sclerosis (MS) and, as in MS, clinical signs of EAE are associated with blood-brain barrier (BBB) disruption. SR 57746A, a nonpeptide drug without classical immunosuppressive properties, efficiently protected the BBB and impaired intrathecal IgG synthesis (two conventional markers of MS exacerbation) and consequently suppressed EAE clinical signs. This compound inhibited EAE-induced spinal cord mononuclear cell invasion and normalized tumor necrosis factor alpha and IFN-gamma mRNA expression within the spinal cord. These data suggested that pharmacological intervention aimed at inhibiting proinflammatory cytokine expression within the central nervous system provided protection against BBB disruption, the first clinical sign of EAE and probably the key point of acute MS attacks. This finding could lead to the development of a new class of compounds for oral therapy of MS, as a supplement to immunosuppressive agents.
Bourrié
B
B
Department of Immunopharmacology, Sanofi Recherche, 371 rue du Pr. J. Blayac, 34184 Montpellier, France.
Bribes
E
E
Esclangon
M
M
Garcia
L
L
Marchand
J
J
Thomas
C
C
Maffrand
J P
JP
Casellas
P
P
D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D008070:Lipopolysaccharides / Q000008:administration & dosage; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D008070:Lipopolysaccharides; D009281:Naphthalenes; D018696:Neuroprotective Agents; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C462299:xaliproden