The acute and chronic phases of chronic relapsing experimental autoimmune encephalomyelitis (CR EAE) are ameliorated by the peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinatoiron (III) chloride, (FeTPPS).
There is increasing evidence that the oxidative radical, peroxynitrite (ONOO(-)), is involved in the pathogenesis of inflammatory diseases including multiple sclerosis and the animal counterpart, experimental autoimmune encephalomyelitis (EAE). Compounds that impede the actions of ONOO(-) have proved useful in the control of EAE. In particular, catalytic isomerisation of ONOO(-) to inactive nitrate, through the use of metalloporphyrins, curtails the cellular response to inflammatory stimuli and halts the progression of neuroinflammation during EAE. The present study examined the pharmacological effects of the metalloporphyrin and ONOO(-) decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinatoiron(III)chloride (FeTPPS) on the acute and relapse phases of chronic relapsing (CR) EAE. Administration of FeTPPS to CR EAE-inoculated Biozzi mice commenced either therapeutically and immediately prior to the emergence of acute or relapse symptoms, or prophylactically, from the onset of remission of acute neurological signs. Drug therapy reduced acute and relapse symptoms but, and in contrast to the former phase, was of limited benefit in preventing histological changes during the latter stage of disease. In contrast, prophylactic FeTPPS was effective in limiting CNS pathology and neurological deficits. The findings confirm the inhibitory effects of FeTPPS on acute stage EAE. Moreover, the study extends previous observations by verifying compound efficacy on relapsing disease. Use of metalloporphyrins, such as FeTPPS, again highlights the important role played by ONOO(-) in the development of inflammatory diseases such as EAE.
Bolton
Christopher
C
Centre for Biochemical Pharmacology, John Vane Science Centre, The William Harvey Research Institute, St. Bartholomew's, The London and Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, UK. c.bolton@qmul.ac.uk
Scott
Gwen S
GS
Smith
Terence
T
Flower
Roderick J
RJ
D000208:Acute Disease; D000818:Animals; D002384:Catalysis; D002908:Chronic Disease; D018450:Disease Progression; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D007536:Isomerism; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D038602:Mice, Biozzi; D030421:Peroxynitrous Acid / Q000378:metabolism*; D012008:Recurrence
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid