Introdaction: Experimental allergic encephatomyelitis (EAE) and it's human counterpart, multiple sclerosis (MS), are central nervous system (CNS) disorders of unknown aetiology. Much evidence exists implicating a role for inflammatory mediators in the pathogencsis of EAE [Hartung et al. J. Neuroimmunol. 1992; 40: 197]. Furthermore, recent investigations have demonstrated peroxynitrite involvement in disease development [Hooper et al. Proc. Natl. Acad. Sci USA 1997; 94: 2528-2533). Although peroxynitrite has been proposed as a mediator of EAE die precise mechanisms through which the molecule exerts its effects remain undefined. Previous studies have demonstrated that peroxynitrite can cause cytotoxicity via DNA single strand-breakage and poly (ADP-ribose) synthetase (PARS) activation [Szabó et al. Proc. NatL Acad. Sci. USA 1996; 93: 1753-1758]. We have, therefore, examined the effect of the novel PARS inhibitor, 5-iodo-6-tmino-1 1,2-beozopyrone (INH2BP) [Szabó et al. Int J. Oncol. 1997; 10: 1093] on the neurological development of EAE. Methods: Male Lewis rats (200-250g) inoculated for EAE were orally administered INH2BP (200mg/kg body weight) or vehicle (0.5 % rocthylcdhuose) once daily from days 7 to 11 post-inoculation (P.L). Animals neurological disease signs were leuiued daily on a severity scale from 0 to 4 [Scott et al., Inflamm. Res. 19%; 45: 524]. Results: Table: Neurological disease symptoms in EAE-sensitised Lewis rats following treatment with INH2BP or vehicle Group Incidence of Mean Day of Mean Number of EAE Disease Disease Rats Onset Severity Paralysed/To ± S.E.M. ± S.E.M. tal Vehicle 8/8 11 ± 0.2 2.3 ± 0.2 2/8 INH2BP 5/8 13 ± 0.5 0.9 ± 0.30/8p<0.01 Mann Whitney U test Conclusions: In conclusion, administration of INH2BP suppressed the development of neurolgical signs of EAE Thus, our data indicate the involvement of PARS activation in the pathogenesis of this disease. Further work is required to rally elucidate the precise role of PARS activation in the aetiology of EAE.
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine