norisoboldine and Inflammation

Norisoboldine (NOR), the primary isoquinoline alkaloid constituent of the root of Lindera aggregata, has previously been demonstrated to attenuate osteoclast (OC) differentiation. Accumulative evidence has shown that aryl hydrocarbon receptor (AhR) plays an important role in regulating the differentiation of various cells, and multiple isoquinoline alkaloids can modulate AhR. In the present study, we explored the role of NOR in the AhR signaling pathway. These data showed that the combination of AhR antagonist resveratrol (Res) or α-naphthoflavone (α-NF) nearly reversed the inhibition of OC differentiation through NOR. NOR could stably bind to AhR, up-regulate the nuclear translocation of AhR, and enhance the accumulation of the AhR-ARNT complex, AhR-mediated reporter gene activity and CYP1A1 expression in RAW 264.7 cells, suggesting that NOR might be an agonist of AhR. Moreover, NOR inhibited the nuclear translocation of NF-κB-p65, resulting in the evident accumulation of the AhR-NF-κB-p65 complex, which could be markedly inhibited through either Res or α-NF. Although NOR only slightly affected the expression of HIF-1α, NOR markedly reduced VEGF mRNA expression and ARNT-HIF-1α complex accumulation. In vivo studies indicated that NOR decreased the number of OCs and ameliorated the bone erosion in the joints of rats with collagen-induced arthritis, accompanied by the up-regulation of CYP1A1 and the down-regulation of VEGF mRNA expression in the synovium of rats. A combination of α-NF nearly completely reversed the effects of NOR. In conclusion, NOR attenuated OC differentiation and bone erosion through the activation of AhR and the subsequent inhibition of both NF-κB and HIF pathways.

Topics: Alkaloids; Animals; Arthritis; Cell Differentiation; Cell Line; Inflammation; Lindera; Male; Mice; Osteoclasts; Plant Extracts; RANK Ligand; Rats; Rats, Wistar; Receptors, Aryl Hydrocarbon; Signal Transduction

Norisoboldine (NOR) is a benzylisoquinoline alkaloid isolated from Radix Linderae, a traditional Chinese medicine. Our previous studies have demonstrated that it produces anti-inflammatory and anti-rheumatoid arthritis effects.. The present study was undertaken to explore the analgesic effects of NOR and its potential mechanism in the formalin test and the acetic acid writhing test.. Oral administration of NOR dose dependently attenuated the formalin-induced pain responses in the second phase, and reduced formalin-induced paw oedema. It also diminished acetic acid-induced writhing responses but had no effect on acute thermal pain in the hotplate test. The mechanistic studies suggested that the adenosine system, but not the opioid receptor system, is involved in NOR-induced antinociception. Naloxone, a non-selective opioid receptor antagonist, had no effect on NOR-induced analgesic action. However, caffeine (a non-selective adenosine receptor antagonist) completely reversed the analgesic effect of NOR in formalin-induced nociceptive responses in the second phase, and 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, a selective adenosine A1 receptor antagonist) completely inhibited NOR-induced analgesia in both formalin-induced nociceptive responses and acetic acid-induced writhing responses. In addition, NOR reduced formalin-induced activation of extracellular signal-regulated kinase and calcium/calmodulin-dependent protein kinase II in the spinal cord, which is also blocked by DPCPX. Furthermore, NOR decreased forskolin-evoked cyclic adenosine monophosphate levels in mouse spinal cord neuronal cultures through the adenosine A1 receptor.. Our data demonstrate that NOR produces the analgesic effect in inflammatory pain by a mechanism related to the adenosine system.

Topics: Alkaloids; Analgesics; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Inflammation; Mice; Pain; Receptor, Adenosine A1; Spinal Cord

Norisoboldine is the main isoquinoline alkaloid occurring in Radix Linderae, the dry roots of Lindera aggregata (Lauraceae family). It has been previously implicated to be able to ameliorate the synovial inflammation and abnormal immune conditions in collagen-induced arthritis of mice. To get insight to the potential anti-inflammatory mechanisms of this alkaloid compound, the present study was undertaken to explore the effects of norisoboldine on the production of pro-inflammatory cytokines from macrophages stimulated by lipopolysaccharide. In vitro, norisoboldine substantially reduced the production of nitric oxide (NO), tumor necrosis factor (TNF)-α as well as interleukin (IL)-1β from RAW264.7 macrophage cells in a concentration-dependent manner, whereas it only slightly reduced the production of interleukin-6 (IL-6) at both protein and transcription levels. Of note, the preventive effects of norisoboldine on the release of pro-inflammatory cytokines were correlated with the inhibitory action on the phosphorylations of mitogen-activated protein (MAP) kinases including p38, extracellular signal-regulated kinase (ERK) and c-jun NH(2)-terminal kinase (JNK), but not on the activation and translocation of nuclear factor-κB (NF-κB). It can be therefore concluded that norisoboldine inhibits the macrophage activation and the resultant production of pro-inflammatory cytokines via down-regulating the activation of MAPKs signaling pathways rather than NF-κB.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Inflammation; Interleukin-1beta; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide; Phosphorylation; Tumor Necrosis Factor-alpha