Anti-Inflammatory Effects of Boldine and Reticuline Isolated from Litsea cubeba through JAK2/STAT3 and NF-κB Signaling Pathways

Abstract

The anti-inflammatory effects of boldine and reticuline isolated from <i>Litsea cubeba</i> were evaluated by using xylene-induced ear edema and carrageenan-induced paw edema in mice and rats. Our results demonstrated that intragastric administration with boldine and reticuline significantly mitigated ear weight in mice and decreased paw volume in rats. A combination administration of boldine (0.5 mg/kg) + reticuline (0.25 mg/kg) resulted in a potentiated inhibition in these two models. In parallel, boldine or reticuline reduce the infiltration of neutrophil leukocytes in rat paw tissue, respectively, and the combination of the two groups performed a better anti-inflammatory activity as shown in histopathologies. Boldine, reticuline, and their combination notably inhibited mRNA expressions of TNF-<i>α</i>, and IL-6 and reduced the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Beyond that, their combination also can reduce the phosphorylation levels of p65 and I<i>κ</i>B<i>α</i> in the pathological tissues of animals, as observed by real-time PCR and western blot analyses, respectively. These findings indicate for the first time that boldine and reticuline have not only anti-inflammatory activity but also potential synergistic effects <i>in vivo</i>. The underlying mechanism may relate to the inhibition on the expression of pro-inflammatory cytokines, such as TNF-<i>α</i> and IL-6, which may be a consequence of JAK2/STAT3 and NF-<i>κ</i>B pathway involvements. This study provides useful data for further exploration and application of boldine and reticuline as potential anti-inflammatory medicines.