Effects of Koumine on Adjuvant- and Collagen-Induced Arthritis in Rats

Yang, Jian; Cai, Hong-da; Zeng, Yue; Chen, Zehong; Fang, Menghan; Su, Yanping; Huang, Huihui; Xu, Ying; Yu, Chang‐Xi

doi:10.1021/acs.jnatprod.6b00554

Cited by 45 publications

(40 citation statements)

References 43 publications

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“…Koumine (KM), the most abundant alkaloid in Gelsemium elegans Benth. ( G. elegans ) has various pharmacological properties and is known to be effective in the treatment of numerous age-associated conditions including postoperative pain ( Xiong et al., 2017 ; Shoaib et al., 2019 ), inflammation ( Yuan et al., 2016 ; Wu et al., 2020 ), rheumatoid arthritis ( Yang et al., 2016 ), malignant tumors ( Yuan et al., 2019a ), nonalcoholic fatty liver disease ( Yue et al., 2019 ), oxidative stress ( Yuan et al., 2019b ), and neuropathic pain ( Jin et al., 2018a ; Jin et al., 2018b ). However, the pharmacokinetic profile of KM in the elderly or aged animals remains to be fully evaluated.…”

Section: Introductionmentioning

confidence: 99%

Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Zhang

et al. 2020

Front. Pharmacol.

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Aging leads to changes in nearly all pharmacokinetic phases. Koumine (KM), an alkaloid derived from Gelsemium elegans Benth., is effective against age-associated chronic diseases, but its dose proportionality following oral administration in aged individuals remains unknown. Herein, we established and validated a simple method that requires low sample volumes to determine KM concentration in rats using ultra-performance liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (C max) of 7 mg•kg −1 KM was~12-fold and~24-fold higher than that of 0.28 mg•kg −1 KM in adult and aged rats, respectively (P < 0.01). Time to reach C max (T max) for 7 mg•kg −1 KM was 4-fold longer in aged rats (P < 0.05). The area under the curve (AUC) of 7 mg•kg −1 KM was >17-fold and >43-fold higher than those of 0.28 mg•kg −1 KM in adult and aged rats, respectively (P < 0.01). The half-life (t 1/2) of 7 mg•kg −1 KM was over 4-fold longer than that of 0.28 mg•kg −1 KM in adult rats (P < 0.01). The t 1/2 of 1.4 and 7 mg•kg −1 KM were 1.5~2fold longer, than that of 0.28 mg•kg −1 KM in aged rats (P < 0.05). The clearance rate of 7 mg•kg −1 KM was significantly lower in aged than in adult rats (P < 0.05). For 7.0 mg•kg −1 KM, the C max in aged rats was higher than in adult rats during the T max period (P < 0.05). In aged rats, the AUC for KM was >2.5-fold higher (P < 0.05) and the t 1/2 was >60% longer than in adult rats (P < 0.05). These results help interpret the pharmacokinetics of KM in aging-associated diseases.

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Section: Introductionmentioning

confidence: 99%

Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Zhang

et al. 2020

Front. Pharmacol.

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“…We recently reported the analgesic effect of koumine in various animal pain models, such as chronic constriction injury (CCI), spared nerve injury, diabetic NP, and rheumatoid arthritis pain models (Xu et al, 2012; Ling et al, 2014; Qiu et al, 2015; Yang et al, 2016; Xiong et al, 2017; Jin et al, 2018a). Koumine displayed high efficiency and low toxicity in the treatment of NP, implying that this compound may have potential as a new anti-NP drug.…”

Section: Introductionmentioning

confidence: 99%

Koumine Decreases Astrocyte-Mediated Neuroinflammation and Enhances Autophagy, Contributing to Neuropathic Pain From Chronic Constriction Injury in Rats

Jin

Yue

et al. 2018

Front. Pharmacol.

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Koumine, an indole alkaloid, is a major bioactive component of Gelsemium elegans. Previous studies have demonstrated that koumine has noticeable anti-inflammatory and analgesic effects in inflammatory and neuropathic pain (NP) models, but the mechanisms involved are not well understood. This study was designed to explore the analgesic effect of koumine on chronic constriction injury (CCI)-induced NP in rats and the underlying mechanisms, including astrocyte autophagy and apoptosis in the spinal cord. Rats with CCI-induced NP were used to evaluate the analgesic and anti-inflammatory effects of koumine. Lipopolysaccharide (LPS)-induced inflammation in rat primary astrocytes was also used to evaluate the anti-inflammatory effect of koumine. We found that repeated treatment with koumine significantly reduced and inhibited CCI-evoked astrocyte activation as well as the levels of pro-inflammatory cytokines. Meanwhile, we found that koumine promoted autophagy in the spinal cord of CCI rats, as reflected by decreases in the LC3-II/I ratio and P62 expression. Double immunofluorescence staining showed a high level of colocalization between LC3 and GFAP-positive glia cells, which could be decreased by koumine. Intrathecal injection of an autophagy inhibitor (chloroquine) reversed the analgesic effect of koumine, as well as the inhibitory effect of koumine on astrocyte activation in the spinal cord. In addition, TUNEL staining suggested that CCI-induced apoptosis was inhibited by koumine, and this inhibition could be abolished by chloroquine. Western blot analysis revealed that koumine significantly increased the level of Bcl-xl while inhibiting Bax expression and decreasing cleaved caspase-3. In addition, we found that koumine could decrease astrocyte-mediated neuroinflammation and enhance autophagy in primary cultured astrocytes. These results suggest that the analgesic effects of koumine on CCI-induced NP may involve inhibition of astrocyte activation and pro-inflammatory cytokine release, which may relate to the promotion of astrocyte autophagy and the inhibition for apoptosis in the spinal cord.

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“…Several potential pharmaceutical roles for koumine have been identified, including anxiolytic, antitumor, antistress, antipsoriatic, and analgesic activities [ 14 – 18 ]. In previous studies, we found that koumine plays a significant role in the anti-inflammatory and analgesic effects in inflammatory and NP models [ 18 – 21 ]. Interestingly, both the anxiolytic and analgesic effects of koumine may involve the modulation of neurosteroids in the spinal cord [ 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Koumine Attenuates Neuroglia Activation and Inflammatory Response to Neuropathic Pain

Jin

Lin

et al. 2018

Neural Plasticity

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Despite decades of studies, the currently available drugs largely fail to control neuropathic pain. Koumine—an alkaloidal constituent derived from the medicinal plant Gelsemium elegans Benth.—has been shown to possess analgesic and anti-inflammatory properties; however, the underlying mechanisms remain unclear. In this study, we aimed to investigate the analgesic and anti-inflammatory effects and the possible underlying mechanisms of koumine. The analgesic and anti-inflammatory effects of koumine were explored by using chronic constriction injury of the sciatic nerve (CCI) neuropathic pain model in vivo and LPS-induced injury in microglia BV2 cells in vitro. Immunofluorescence staining and Western blot analysis were used to assess the modulator effect of koumine on microglia and astrocyte activation after CCI surgery. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the levels of proinflammatory cytokines. Western blot analysis and quantitative real-time polymerase chain reaction (qPCR) were used to examine the modulator effect of koumine on microglial M1 polarization. We found that single or repeated treatment of koumine can significantly reduce neuropathic pain after nerve injury. Moreover, koumine showed inhibitory effects on CCI-evoked microglia and astrocyte activation and reduced proinflammatory cytokine production in the spinal cord in rat CCI models. In BV2 cells, koumine significantly inhibited microglia M1 polarization. Furthermore, the analgesic effect of koumine was inhibited by a TSPO antagonist PK11195. These findings suggest that the analgesic effects of koumine on CCI-induced neuropathic pain may result from the inhibition of microglia activation and M1 polarization as well as the activation of astrocytes while sparing the anti-inflammatory responses to neuropathic pain.

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Effects of Koumine on Adjuvant- and Collagen-Induced Arthritis in Rats

Cited by 45 publications

References 43 publications

Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Koumine Decreases Astrocyte-Mediated Neuroinflammation and Enhances Autophagy, Contributing to Neuropathic Pain From Chronic Constriction Injury in Rats

Koumine Attenuates Neuroglia Activation and Inflammatory Response to Neuropathic Pain

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