|Toxicol Appl Pharmacol. 2015 Jan 1;282(1):90-9. |
|Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues.[Pubmed: 25481498]|
|Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic-pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail.
METHODS AND RESULTS:
In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3(+) cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint.
The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR.
|Acta Pharmacol Sin. 2013 Mar;34(3):403-13. |
|Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE(2), and MMP-13 expression.[Pubmed: 23396374 ]|
|To explore the effects of Norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms.
METHODS AND RESULTS:
AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR.
In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE2, and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins.
NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE2, and MMP-13 expression via the p38/ERK/AKT/AP-1 pathway.