Bushen Zhuangjin Decoction (BZD) are an herbal compound commonly used to treat osteoarthritis (OA) in China. This study aimed to verify the mechanism of Bushen Zhuangjin Decoction in relieving the pain of knee osteoarthritis. Network pharmacology evaluation was used to discover the potential targets of BZD to relieve pain in KOA. The therapeutic effects of BZD treatment on KOA pain using histomorphology, behavioral assessments, suspension chip analysis, and ultra-high performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) assays. The functional magnetic resonance imaging was used to explore the effects of BZD treatment on brain function associated to KOA. Network pharmacological analysis revealed the association between the analgesic effect of BZD on KOA and the pain signaling neurotransmitter 5-HT. Subsequently, we conducted experiments to verify the therapeutic effect of BZD on pain in KOA animal models. Behavioral tests demonstrated that the pain threshold of knee osteoarthritis rats decreased in PWT and PWL, but BZD was able to increase the pain threshold. Histopathological staining indicated thinning of the cartilage layer and sparse trabeculae in the subchondral bone. Suspension chip analysis revealed a significant increase in pro-inflammatory factors of IL-1α, IL-5, IL-12, IL-17A, RANTES, TNF-α and M-CSF in KOA, along with a significant decrease in anti-inflammatory factor of IL-13. However, BZD treatment decreased the expression of pro-inflammatory factors and increased the content of anti-inflammatory factor. UHPLC-MS/MS analysis showed a significant decrease in the serum levels of GABA, E, GSH, Kyn, Met, and VMA in KOA, which were significantly increased by BZD. Conversely, the serum levels of TrpA, TyrA, Spd, and BALa were significantly increased in KOA and significantly decreased by BZD. ELISA and Western blot analysis showed increased expression of subchondral bone pain-related neuropeptides SP, CGRP, TH, NPY, VEGFA, 5-HT3 in KOA, which were decreased in BZD. Functional magnetic resonance imaging demonstrated that BZD exerts its therapeutic effect on KOA by modulating the activity and functional connections of the cortex, hypothalamus, and hippocampus. This study confirmed the significant role of pain-related neuromodulation mechanisms in the analgesic therapy of BZD and provides a theoretical foundation for using BZD as a traditional Chinese medical treatment for KOA pain.
Abstract Chronic pain is the principal clinical manifestation of knee osteoarthritis (KOA) and an essential indicator of the diagnosis and treatment effect. Changes in brain functional activity are related with chronic pain in KOA. Bushen Zhuangjin Decoction (BZD) has been proved to reduce inflammation of arthritis, improve cartilage degeneration and analgesia, but whether it plays a role through the change of brain function activity is not clear. Here, three experiments were performed: (1) network pharmacology evaluation to discover the potential targets of BZD to relieve pain in KOA; (2) verification of the therapeutic effects of BZD treatment on KOA pain with histomorphology, behavioral assessments, suspension chip analysis, and ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) assays; and (3) functional magnetic resonance imaging to explore the effects of BZD treatment on brain function associated to KOA. The analgesic effect of BZD on KOA was found to be related to the neurotransmitters of pain signals through network pharmacology and the therapeutic effect of BZD on KOA pain was verified in vivo, and related to neuropeptides and neurotransmitters. Functional magnetic resonance imaging showed that BZD treatment could reverse the regional homogeneity/amplitude of low-frequency fluctuation analysis in pain-related brain regions of KOA, suggesting that the analgesic mechanism of BZD is related to neural regulation. This study confirmed the key position of pain-related neuromodulation mechanisms in the analgesic therapy of BZD and provide a theoretical basis for the treatment of KOA pain with BZD as a traditional Chinese medical.
Ethnopharmacological relevance: Bushen Zhuangjin Decoction (BZD) are an herbal compound commonly used to treat osteoarthritis (OA) in China.Aim of the studyThis study aimed to verify the mechanism of Bushen Zhuangjin Decoction in relieving the pain of knee osteoarthritis.Materials and methods: Network pharmacology evaluation was used to discover the potential targets of BZD to relieve pain in KOA. The therapeutic effects of BZD treatment on KOA pain using histomorphology, behavioral assessments, suspension chip analysis, and ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) assays. The functional magnetic resonance imaging was used to explore the effects of BZD treatment on brain function associated to KOA.Results: The analgesic effect of BZD on KOA was found to be related to the neurotransmitters of pain signals through network pharmacology and the therapeutic effect of BZD on KOA pain was verified in vivo, and related to neuropeptides and neurotransmitters. Functional magnetic resonance imaging showed that BZD treatment could reverse the regional homogeneity/amplitude of low-frequency fluctuation analysis in pain-related brain regions of KOA, suggesting that the analgesic mechanism of BZD is related to neural regulation.Conclusions: This study confirmed the key position of pain-related neuromodulation mechanisms in the analgesic therapy of BZD and provide a theoretical basis for the treatment of KOA pain with BZD as a traditional Chinese medical.
ABSTRACT Knee osteoarthritis (KOA) is a chronic degenerative joint disease‐causing chronic pain and disability. Neuromodulation of subchondral bone affects KOA‐related pain and involves dorsal root ganglion (DRG). Our previous studies have demonstrated efficacy of icariin (ICA) in treating KOA, but neuromodulation mechanisms in peripheral nerves associated with the treatment of chronic pain in KOA remain unclear. This study aimed to investigate peripheral neuromodulation mechanisms of ICA in KOA‐related chronic pain: (1) assessing therapeutic effect of ICA in a rat model of KOA‐induced chronic pain; (2) investigating changes in pain‐related nerve fibres and transient receptor potential vanilloid Subfamily 1 (TRPV1) pathway in subchondral bone following ICA treatment; and (3) exploring expression of pain‐related Nogo‐A/TRPV1 pathway in DRG, thereby elucidating neurotransmission of pain. Experimental results confirmed the curative effect of ICA on KOA by relieving chronic pain and pathological changes. ICA also effectively reduced bone remodelling, the area of pain‐related positive nerve fibres and expression of TRPV1 in subchondral bone. Furthermore, ICA downregulated pain‐related Nogo‐A/TRPV1 pathway in the DRG. These findings provide new mechanistic insights into the therapeutic potential of ICA in relieving peripheral nervous system‐related chronic pain in KOA.
Knee osteoarthritis (KOA) is a common disease with no specific treatment. Icariin (ICA) is considered an agent for KOA. This study aimed to confirm the pain-related neuromodulation mechanisms of ICA on KOA. Three experiments were designed: (1) verifying the therapeutic effects of ICA in vivo and in vitro, (2) exploring the potential pain-related neuromodulation pathways involved in ICA treatment by functional magnetic resonance imaging (fMRI) and virus retrograde tracing (VRT) and (3) confirming the pain-related targets by tandem mass tag (TMT)-based quantitative proteomics and bioinformatic analyses. Experiment 1 verified the efficacy of ICA in OA animal and cell models. Experiment 2 found a series of brain regions associated with KOA reversed by ICA treatment, indicating that a pain-related hypothalamic-mediated neuromodulation pathway and an endocannabinoid (EC)-related pathway contribute to ICA mechanisms. Experiment 3 explored and confirmed four pain-related genes involved in KOA and ICA treatment. We confirmed the key role of pain-related neuromodulation mechanisms in ICA treatment associated with its analgesic effect. Our findings contribute to considering ICA as a novel therapy for KOA.
Osteoarthritis (OA) is a common joint disease characterized by chronic pain, and the perception of pain is closely associated with brain function and neuropeptide regulation. Rehmannia is common plant herb with anti-inflammatory and analgesic properties that is used to treat OA. However, it is unclear whether Rehmannia alleviates OA-related pain via regulation of neuropeptides and brain function. We examined the pain relief regulatory pathway in OA after treatment with Rehmannia by verifying the therapeutic effect of Rehmannia alcohol extract in vivo and vitro and exploring of the potential mechanism underlying the analgesic effect of Rahmanian using functional magnetic resonance imaging and measuring neuropeptide secretion. Our results showed that Rehmannia alcohol extract and the related active ingredient, Rehmannioside D, can delay cartilage degradation and alleviate inflammation in OA rats. The Rehmannia alcohol extract can also relieve OA pain, reduce the secretion of calcitonin gene-related peptide (CGRP) and substance P (SP), and reverse the pathological changes in the cerebral cortex and hippocampus. Our research results demonstrate that Rehmannia alleviates OA pain by protecting cartilage, preventing the stimulation of inflammatory factors on neuropeptide secretion, and influencing the relevant functional areas of the brain.
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