Sinomenine

The herb of Sinomenium acutum Rehd. Et Wils.

Sinomenine inhibits microglia activation and attenuates brain injury in intracerebral hemorrhage.[Pubmed:24815539]

Mol Immunol. 2014 Aug;60(2):109-14.

Intracerebral hemorrhage (ICH) causes morbidity and mortality and commonly follows the reperfusion after an ischemic event. Microglial activation mediated cytokine and protease secretion contributes to brain injury in ICH. Previous studies have shown that Sinomenine possesses potent immunoregulatory properties. However, little is known about its exact role in ICH. In the present study, to investigate the effect of Sinomenine on microglial cells inflammation, we treated ICH-challenged BV2 microglial cells with Sinomenine in vitro, and explored its neuroprotection role in intracerebral hemorrhage in vivo. Changes in inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6, reactive oxygen species (ROS) and NF-kappaB activation NF-kappaB were observed. In addition, the neurological deficit and cerebral water content of ICH mice were studied. The results demonstrated that Sinomenine could inhibit the release of these cytokines and attenuate ROS production in a dose-dependent manner, and reduce NF-kappaB activation. Furthermore, Sinomenine markedly inhibited cerebral water content and neurological deficit. In conclusion, our findings suggest that Sinomenine played the protective effects through inhibition of microglial inflammation, and the findings also provided a novel therapy to treat ICH induced brain injury.

Sinomenine attenuates 2, 4, 6-trinitrobenzene sulfonic acid-induced colitis in mice.[Pubmed:17386408]

Int Immunopharmacol. 2007 May;7(5):604-11.

Sinomenine is a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum. It was demonstrated that Sinomenine had anti-inflammatory and immunosuppressive effects in the previous studies. The aim of the present study was to evaluate therapeutic effects of Sinomenine on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) induced colitis in mice. Two hours following colonic instillation of TNBS, Sinomenine with several doses (30, 100, 200 mg/kg) was given by gastric gavage once daily for 7 days. Comparing with the saline-treated mice with TNBS-induced colitis, Sinomenine (100 mg/kg and 200 mg/kg)-treated mice with TNBS-induced colitis were shown improvements of weight loss, macroscopic score, histological score, and myeloperoxidase activity. Moreover, treatments with Sinomenine (100 mg/kg and 200 mg/kg) decreased the up-regulated mRNA and protein levels of tumour necrosis factor-alpha(TNF-alpha) and interferon-gamma (IFN-gamma) caused by TNBS. Our findings suggest that Sinomenine attenuates TNBS-induced colitis in mice and the therapeutic mechanism might be related to the reduction of up-regulated colonic TNF-alpha and IFN-gamma production caused by TNBS.

Sinomenine reduces iNOS expression via inhibiting the T-bet IFN-gamma pathway in experimental autoimmune encephalomyelitis in rats.[Pubmed:23554784]

J Biomed Res. 2012 Nov;26(6):448-55.

Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that Sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis (EAE) in rats. In this study, we further investigated the mechanisms of Sinomenine treatment in EAE rats. In EAE rats, treatment with Sinomenine exerted an anti-inducible NO synthase (anti-iNOS) effect, which is related to the reductions of Th1 cytokine interferon-gamma (IFN-gamma) and its transcription factor, T-bet, in spinal cords. Moreover, Sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat interleukin 12 reduced the expression of T-bet and IFN-gamma in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, Sinomenine had no direct inhibitory effect on iNOS produced by astrocytes cultured with IFN-gamma and tumor necrosis factor alpha in vitro. In conclusion, the anti-iNOS effect of Sinomenine on EAE is mediated via the suppression of T-bet /IFN-gamma pathway.

Sinomenine suppresses collagen-induced arthritis by reciprocal modulation of regulatory T cells and Th17 cells in gut-associated lymphoid tissues.[Pubmed:25656802]

Mol Immunol. 2015 May;65(1):94-103.

Sinomenine (SIN) has long been used as a therapeutic agent of rheumatoid arthritis (RA) in China. However, the discrepancy between low oral bioavailability and higher minimal effective concentration made its action mode mysterious. The present study aimed to gain insight into the mechanisms by which SIN suppressed collagen-induced arthritis (CIA) in rats in view of Th17 and regulatory T (Treg) cell balance. SIN was orally administered, and the clinical symptoms of CIA rats were monitored; inflammatory cytokines levels in serum were measured by ELISA; pharmacokinetic studies were performed in normal and CIA rats; Th17 and Treg cell frequencies were analyzed by flow cytometry. The data showed that SIN treatment resulted in a dramatic decrease of arthritis scores and paw volume of CIA rats, which was accompanied by down-regulation of IL-17A and up-regulation of IL-10 in rat serum. The frequency of Treg cells was increased and the frequency of Th17 cells was decreased in the gut lymphoid tissues of SIN-treated rats. Immunohistochemistry assay demonstrated that more alpha4beta7-positive cells were detained in joint tissues after SIN treatment. Moreover, the anti-arthritis efficacy of SIN disappeared when it was given by intraperitoneal injection, further confirming the action of SIN was gut-dependent. In conclusion, SIN exerts anti-RA action probably through modulating the frequencies of Treg cells and Th17 cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from gut to joint.

Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase.[Pubmed:17880684]

J Neuroinflammation. 2007 Sep 19;4:23.

BACKGROUND: The mechanisms involved in the induction and regulation of inflammation resulting in dopaminergic (DA) neurotoxicity in Parkinson's disease (PD) are complex and incompletely understood. Microglia-mediated inflammation has recently been implicated as a critical mechanism responsible for progressive neurodegeneration. METHODS: Mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanisms of Sinomenine (SN)-mediated anti-inflammatory and neuroprotective effects in both the lipopolysaccharide (LPS)- and the 1-methyl-4-phenylpyridinium (MPP+)-mediated models of PD. RESULTS: SN showed equivalent efficacy in protecting against DA neuron death in rat midbrain neuron-glial cultures at both micro- and sub-picomolar concentrations, but no protection was seen at nanomolar concentrations. The neuroprotective effect of SN was attributed to inhibition of microglial activation, since SN significantly decreased tumor necrosis factor-alpha (TNF-alpha, prostaglandin E2 (PGE2) and reactive oxygen species (ROS) production by microglia. In addition, from the therapeutic point of view, we focused on sub-picomolar concentration of SN for further mechanistic studies. We found that 10(-14) M of SN failed to protect DA neurons against MPP+-induced toxicity in the absence of microglia. More importantly, SN failed to show a protective effect in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells. Furthermore, we demonstrated that SN reduced LPS-induced extracellular ROS production through the inhibition of the PHOX cytosolic subunit p47phoxtranslocation to the cell membrane. CONCLUSION: Our findings strongly suggest that the protective effects of SN are most likely mediated through the inhibition of microglial PHOX activity. These findings suggest a novel therapy to treat inflammation-mediated neurodegenerative diseases.

Protection by sinomenine against endotoxin-induced fulminant hepatitis in galactosamine-sensitized mice.[Pubmed:8093093]

Biochem Pharmacol. 1994 Aug 30;48(5):1050-2.

Sinomenine, an epimorphinan alkaloid, was tested for protecting hepatitis induced by lipopolysaccharide (LPS) in galactosamine (GalN)-sensitized mice. Sinomenine protected against the hepatic injuries in the dose range of 10-100 mg/kg in a dose-dependent manner and suppressed the production of tumor necrosis factor (TNF), which appeared in serum earlier than aminotransferases in GalN/LPS-treated mice. Sinomenine significantly suppressed the in vitro production of superoxide anion and hydrogen peroxide in the macrophage cultures stimulated with phorbol 12-myristate acetate. It is discussed that Sinomenine prevents GalN/LPS-treated hepatic failure by suppressing TNF production and/or reactive oxygen generation.

Sinomenine, an alkaloid extracted from Sinomenium acutum, is a blocker of the NF-κB activation. Sinomenine also is an activator of μ-opioid receptor.

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