IBUPROFEN - EFFECT ON INDUCIBLE NITRIC-OXIDE SYNTHASE

Treatment with ibuprofen and other non-steroidal anti-inflammatory dru gs (NSAIDS) has been reported to decrease the incidence as well as slo w down the progression of Alzheimer's disease. Understanding the mecha nism of this therapeutic effect would provide a target for development of drugs which may be devoid of side effects observed with NSAIDs. In addition to inhibiting cyclooxygenase (COX), the NSAIDs have recently been shown to decrease inducible nitric oxide synthase (iNOS) activit y. Ibuprofen and other NSAIDs had no direct effect on catalytic activi ty of iNOS, but decreased levels of iNOS mRNA. The mechanism of action of ibuprofen on reduction of iNOS activity has been further investiga ted in the present study using rat primary cerebellar glial cell cultu res. In addition; the effect of ibuprofen on COX mRNA expression and p rostaglandin information was also studied. Glial cells treated with E. coli lipopolysaccharide (LPS) and interferon gamma (INF gamma) for 16 h expressed iNOS and COX. Ibuprofen did not directly inhibit iNOS act ivity. However, when ibuprofen was incubated at the same time with LPS and INF gamma for 16 h, enzyme activity was reduced, with an IC50 of 0.76 mM. Ibuprofen concentration-dependently decreased iNOS mRNA level s, with an IC50 >2 mM. Thus, there was no correlation between decrease in iNOS activity and reduction in iNOS mRNA levels. Ibuprofen decreas ed iNOS protein levels, as determined by Western blot, with an IC50 of 0.89 mM. The data suggest that the reduction in iNOS activity by ibup rofen is due io inhibition of post-transcriptional processing of this enzyme. Ibuprofen had no effect on constitutive COX (COX-1) or inducib le COX (COX-2) mRNA expression. However, ibuprofen inhibited PGE(2) fo rmation with an IC50 of 0.86 mM. The anti-inflammatory actions of ibup rofen have been related to inhibition of COX and, subsequently, reduci ng prostaglandin formation. Since the potency of ibuprofen for inhibit ion of PGE(2) formation and reduction in iNOS activity are similar, it is suggested that. at therapeutically effective doses, a decrease in iNOS activity may also occur in vivo. Therefore, reduction in iNOS pro tein levels in the brain may have a role in preserving the integrity o f neurons in individuals susceptible to Alzheimer's disease. (C) 1997 Elsevier Science B.V.