A novel calpain inhibitor for the treatment of acute experimental autoimmune encephalomyelitis.
Aberrant activation of calpain plays a key role in the pathophysiology of several neurodegenerative disorders. Calpain is increasingly expressed in inflammatory cells in EAE and is significantly elevated in the white matter of patients with multiple sclerosis, thus calpain inhibition could be a target for therapeutic intervention. The experiments reported here employed a myelin oligodendrocyte glycoprotein-induced disease model in C57Bl/6 mice (EAE) and a novel calpain inhibitor, targeted to nervous tissue. CYLA was found to reduce clinical signs of EAE and prevent demyelination and inflammatory infiltration in a dose- and time-dependent manner. Oral administration of the diacetal prodrug was equally effective.
Hassen
Getaw Worku
GW
SUNY Downstate Medical Center, USA.
Feliberti
Jason
J
Kesner
Leo
L
Stracher
Alfred
A
Mokhtarian
Foroozan
F
D000208:Acute Disease / Q000628:therapy; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007165:Immunosuppression Therapy / Q000379:methods; D018836:Inflammation Mediators / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009842:Oligopeptides; D002154:Calpain