Koumine modulates spinal microglial M1 polarization and the inflammatory response through the Notch-RBP-Jκ signaling pathway, ameliorating diabetic neuropathic pain in rats

Jin, Gui‐Lin; Hong, Limian; Liu, Haiping; Yue, Rongcai; Shen, Zu-Cheng; Yang, Jian; Xu, Ying; Huang, Huihui; Li, Yang; Xiong, Bojun; Su, Yanping; Yu, Chang‐Xi

doi:10.1016/j.phymed.2021.153640

Cited by 25 publications

(16 citation statements)

References 29 publications

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“…Due to its suitable biological activities and few side effects, it has attracted increasing attention from researchers. Previous studies have shown that KM can significantly increase pain thresholds in animals with neuropathic pain by inhibiting glial cell activation in the spinal dorsal horn, and KM administration does not result in tolerance or dependence and is safe (Jin et al, 2018(Jin et al, , 2021Shoaib et al, 2019). In addition, neuropathic pain is often accompanied by comorbidities like anxiety, and we found that KM has a significant anti-anxiety effect (Chen et al, 2017).…”

Section: Introductionsupporting

confidence: 55%

Basolateral amygdala astrocytes modulate of diabetic neuropathic pain and may be a potential therapeutic target for koumine

Yang

Chen

et al. 2022

Preprint

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Background and Purpose: New remedies are required for the treatment of diabetic neuropathic pain (DNP) due to insufficient efficacy of available therapies. Here, we used chemogenetic approaches combined with in vivo pharmacology to elucidate the role of BLA astrocytes in DNP pathogenesis and provide new insights into DNP therapeutic strategies. Experimental Approach: A streptozotocin-induced DNP model was established. Designer receptors exclusively activated by designer drugs (DREADDs) were used to regulate the activity of astrocytes. Mechanical hyperalgesia was assessed using the electronic von Frey test. Anxiety-like behaviors were detected by open field and elevated plus maze tests. Astrocytic activity was detected by immunofluorescence, and cytokine content was determined by ELISA. Key Results: BLA astrocytes were regulated by DREADDs, and inhibition of BLA astrocytes attenuated mechanical allodynia and anxiety-like behavior in DNP rats. Contrastively, temporary activation of BLA astrocytes induced allodynia without anxious behavior in naive rats. In addition, we found that koumine alleviates mechanical allodynia and anxiety-like behavior in DNP rats, inhibits the activation of BLA astrocytes and suppresses the inflammatory response. Furthermore, persistent activation of BLA astrocytes by chemogenetic mimics chronic pain, and koumine can alleviate its pain hypersensitivity and anxiety-like behavior. Conclusion and Implications: DREADDs bidirectionally regulate the activity of BLA astrocytes, which proves for the first time the role of BLA astrocytes activation in the pathogenesis of DNP and represents a novel therapeutic strategy for DNP. Koumine ameliorated DNP, perhaps by inhibiting the activation of BLA astrocytes and reveal KM as a potential candidate for treating DNP.

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Section: Introductionsupporting

confidence: 55%

Basolateral amygdala astrocytes modulate of diabetic neuropathic pain and may be a potential therapeutic target for koumine

Yang

Chen

et al. 2022

Preprint

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“…Abundant of studies 4–8 have identified that after the nerve injury, microglia will be polarized mainly towards M1 subtype, which contributes to the overproduction of series of pro-inflammatory cytokines and finally leads to the allodynia; Besides, treatments targeting on alleviating M1 polarization while restoring M2 polarization have proven to be effective for the pain relief. 45–48 Importantly, Xu et al 6 reported that following chronic sciatic nerve damage, both M1 and M2 subtype microglial genes increased immediately at day one. However, only M1-related genes remained elevation at day seven and thereafter, leaving M2 genes falling to the Sham level.…”

Section: Discussionmentioning

confidence: 99%

The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain

Liu¹,

Sun²,

Xu³

et al. 2022

JIR

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Background Neuropathic pain (NP) is known to be highly correlated with microglial polarization, of which the regulatory mechanism remains to be elucidated. Here, the aim of this study is to further investigate the relationship between bone morphogenetic protein 4 (BMP4) and microglial polarization in the process of NP. Methods Firstly, normal adult rats received intrathecal BMP4 administration to assess BMP4ʹs effect on microglial polarization. Secondly, a BMP4 antagonist – Noggin – was applied to a rat NP model achieved by L5 spinal nerve ligation (SNL) to investigate whether antagonizing BMP4 signaling could alleviate allodynia by reversing the imbalance of the M1/M2 polarization ratio. In both experiments, Von-Frey filaments were used to test the changes in the paw withdrawal threshold (PWT), and Western blotting, immuno-fluorescence, PCR and flow cytometry were further performed to investigate microglial activity and the expression patterns of M1 and M2 markers, respectively. Results Firstly, BMP4 administration induced a significant PWT decrease and microglial activation in normal rats; Western blotting, PCR and flow cytometry further revealed that M1 markers including CD16, MHCII, and TNF-α showed a marked elevation after BMP4 application; while M2 markers, such as Arg-1, CD204 and IL-4, peaked at an early stage (P1 or P4) and then fell to the Sham level on P7, leading to a persistent imbalance of the M1/M2 ratio throughout the 1st week. Secondly, Noggin treatment significantly relieved allodynia and microglial activation in SNL rats. Moreover, Noggin persistently downregulated the M1 marker levels and simultaneously induced a late-stage elevation of M2 markers expressions, thereby reversing the imbalance of the M1/M2 polarization ratio. Conclusion Our results indicate that BMP4 has the ability to induce microglial polarization. Antagonizing BMP4 signaling can relieve pain behavior via mitigating microglial activation and reversing the imbalance of the M1/M2 polarization ratio in the process of NP.

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“…KM is a lipophilic molecule with poor solubility in water (<1 mg/mL). It possesses analgesic, anti-cancer, neuroprotective, immunomodulatory, and anti-inflammatory effects [ 9 , 10 , 11 ]. KM demonstrated a a dose-dependent inhibition of Tetrahymena thermophila proliferation, accompanied by the significant ( p < 0.05) elevation of antioxidant enzyme activity and apoptosis, but induced DNA damage at high concentrations in one study [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Koumine on Growth Performance, Intestinal Morphology, Microbiota, and Intestinal Transcriptional Responses of Cyprinus carpio

Wang

Zuo

et al. 2022

IJMS

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Gelsemium elegans Benth. (GEB) is a traditional medicinal plant in China, and acts as a growth promoter in pigs and goats. Koumine (KM) is the most abundant alkaloid in GEB and produces analgesic, anti-cancer, and immunomodulatory effects. KM can be used as an aquatic immune stimulant, but its growth-promoting effects and transcriptional mechanisms have not been investigated. Diets containing KM at 0, 0.2, 2, and 20 mg/kg were fed to Cyprinus carpio for 71 days to investigate its effects on growth performance, intestinal morphology, microflora, biochemical indicators, and transcriptional mechanisms. Cyprinus carpio fed with KM as the growth promoter, and the number of intestinal crypts and intestinal microbial populations were influenced by KM concentration. KM increased the abundance of colonies of Afipia, Phyllobacterium, Mesorhizobium, and Labrys, which were associated with compound decomposition and proliferation, and decreased the abundance of colonies of pathogenic bacteria Methylobacterium-Methylorubrum. A total of 376 differentially-expressed genes (DEGs) among the four experimental groups were enriched for transforming growth factor-β1 and small mother against decapentaplegic (TGF-β1/Smad), mitogen-activated protein kinase (MAPK), and janus kinases and signal transducers and activators of transcription (Jak/Stat) signaling pathways. In particular, tgfbr1, acvr1l, rreb-1, stat5b, smad4, cbp, and c-fos were up-regulated and positively correlated with KM dose. KM had a growth-promoting effect that was related to cell proliferation driven by the TGF-β1/Smad, MAPK, and Jak/Stat signaling pathways. KM at 0.2 mg/kg optimized the growth performance of C. carpio, while higher concentrations of KM (2 and 20 mg/kg) may induce apoptosis without significantly damaging the fish intestinal structure. Therefore, KM at low concentration has great potential for development as an aquatic growth promotion additive.

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Koumine modulates spinal microglial M1 polarization and the inflammatory response through the Notch-RBP-Jκ signaling pathway, ameliorating diabetic neuropathic pain in rats

Cited by 25 publications

References 29 publications

Basolateral amygdala astrocytes modulate of diabetic neuropathic pain and may be a potential therapeutic target for koumine

Basolateral amygdala astrocytes modulate of diabetic neuropathic pain and may be a potential therapeutic target for koumine

The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain

Effects of Dietary Koumine on Growth Performance, Intestinal Morphology, Microbiota, and Intestinal Transcriptional Responses of Cyprinus carpio

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