ANTISENSE BLOCKADE OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN GLIAL-CELLS DERIVED FROM ADULT SJL MICE

Increasing evidence suggests a correlation between cytokine-induced ni tric oxide synthase (iNOS) and demyelination in Multiple sclerosis (MS ). Inhibition of iNOS may therefore be a novel therapeutic approach in MS. To test an antisense oligodeoxynucleotide (ODN) knockdown strateg y for inhibiting iNOS, we used lipopolysaccharide (LPS) together with gamma-interferon (IFN-gamma) to induce iNOS in adult mouse mixed glial cell cultures. We administered an iNOS-derived antisense phosphorothi orate oligodeoxynucleotide (S-ODN) to block the induction. The antisen se ODN treatment resulted in significant inhibition of LPS and IFN-gam ma induced iNOS mRNA and protein expression. It also inhibited nitric oxide (NO) and cyclic GMP (cGMP) production in a dose dependent fashio n. Sense and random S-oligo had no effect in any of these studies. The se data indicate the efficacy and specificity of the antisense oligode oxynucleotide approach in inhibiting iNOS in glial cells. Copyright (C ) 1996 Elsevier Science Ireland Ltd.