The effects of luteolin on the degrees of inhibition of IL 1?, TNF ? and MMP 9 were significant at concentrations of 0. 2 ?M. These inhibitory values are significantly lower than the selleck Vorinostat respective values observed with quercetin in our previous study. The immunomodulatory effects of luteolin at these low concentrations are especially encour aging since these fall in the realm of plasma concentra tions of approximately 1. 5 ?M observed with supplementation of 1 gday Inhibitors,Modulators,Libraries flavonoids. The pharmacological actions Inhibitors,Modulators,Libraries of luteolin, combined with its enhanced potency, may be especially attractive in the treatment of MS since, beyond the modulation of periph eral immune cells, luteolin has also been shown to exert immunomodulatory effects inhibiting LPS induced microglial activation both in vitro and in vivo.
The immunomodulatory effects of luteolin on CNS resident cells are likely to result in neuroprotection, Inhibitors,Modulators,Libraries since there is a linear relationship between extent of microglial activa tion, demyelination and axonal injury. Similar neu roprotective effects of luteolin have also been observed in rat neural PC12 and glial C6 cells in culture, and in an in vivo model of permanent middle cerebral artery occlusion. TIMP 1 ratios are significantly altered in MS lesions and changes in MMP 9 levels are known Inhibitors,Modulators,Libraries to contribute to the disruption of the blood brain barrier and degradation of extra cellular matrix, activities which are regulated by its endogenous inhibitor TIMP 1. Furthermore, MMP 9 can directly cause axonal injury, independent of its effect on blood brain barrier integrity.
Pharmacological effects of flavonoids seem to be depend ent on specific structural Inhibitors,Modulators,Libraries features of individual flavonoids. Analysis of structure activity relationships indicate that the immunomodulatory effects of flavonoids depend on the position, number and substitution of the hydroxyl group of the B ring, and on saturation of the C2 C3 bond. Although quercetin and luteolin have similar structures, the lack of the hydroxyl group at the C 3 position of luteolin may account for the enhanced immunomodulatory effects observed in this study, as well as luteolins superior ability to inhibit myelin phagocyto sis by macrophages, when compared selleck kinase inhibitor to quercetin. The immunomodulatory effects of luteolin and related flavonoids has been attributed mainly to the regulation of signaling pathways involving nuclear factor kappaB activation and mitogen activated protein kinase family phosphorylation. However, mitogen induction of NF kappaB involves many steps including mitogen induced IkappaB kinase activa tion, IkappaB degradation, DNA binding activity of NF kappaB complex and its nuclear translocation.