Journal of Neuroinflammation
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2025
·Vol. 22
·期 1
·1-22
·
IF 10.1
Zhou Yanjie,Chen Wu,Zhang Yu,Yang Liu,Lu Fu,Yan Wen,Xie Qingfang,Huang Ying,Huang Wanbin,Wang Lintao,Zeng Ziming,Xiao Zheman
Background Caveolin-1 (CAV1), a scaffolding protein critical for caveolae formation, regulates G-protein-coupled receptor (GPCR) signaling via caveolae-mediated endocytosis. The calcitonin receptor-like receptor (CLR), a GPCR and core subunit of the calcitonin gene-related peptide (CGRP) receptor, is a therapeutic target for migraine. However, the role of CAV1 in CLR regulation and migraine remains unclear.Methods A migraine model was established in female mice via dural inflammatory soup (IS) application. Migraine-like behaviors were assessed using Von Frey filament, spontaneous pain behavior counts, light/dark box, and acetone test. CAV1 was overexpressed by lentivirus and downregulated by small interfering RNA (siRNA) technology. Methyl-β-cyclodextrin (MβCD) was used to inhibit caveolae-mediated endocytosis. The molecular mechanism of CAV1 on CLR and neuroinflammation was investigated using biochemistry, multiplex immunohistochemistry staining, internalization assay, and co-immunoprecipitation.Results Repeated IS stimulation elevated CLR expression and internalization in the trigeminal nucleus caudalis (TNC), concurrently activating ERK/CREB signaling, promoting microglial activation, and increasing inflammatory cytokines (TNFα, IL-1β). CAV1 directly interacted with CLR, promoting its degradation. CAV1 knockdown in the TNC exacerbated migraine pathology, characterized by CLR accumulation, enhanced ERK/CREB phosphorylation, and amplified neuroinflammation. Conversely, CAV1 overexpression or MβCD-mediated caveolae disruption normalized CLR levels, reduced signaling hyperactivity, and reversed nociceptive behaviors.Conclusion CAV1 negatively regulates CLR stability, suppressing ERK/CREB signaling and microglial inflammation in a preclinical female migraine model. These findings suggest that CAV1 contributes to migraine-related hyperalgesia and may represent a novel therapeutic target for migraine treatment.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Brain Sciences
·
2023
·Vol. 13
·期 4
·541
·
IF 3.3
Min Zhou,Fang Pang,Dongmei Liao,Xinlu He,Yunhao Yang,Chenglin Tang
Background: Multiple studies have suggested that paralgesia (hyperalgesia and cutaneous allodynia) in migraine reflects the activation and sensitisation of the trigeminovascular system (TGVS). In particular, it reflects the second-order and higher nerve centre sensitisation, which is caused and maintained by neuroinflammation. Microglia activation leads to the release of proinflammatory cytokines involved in inflammatory responses. Accumulating evidence indicates that electroacupuncture (EA) is effective in ameliorating paralgesia, but the underlying mechanisms of EA in migraine attacks caused by microglia and microglia-mediated inflammatory responses are still unclear. The purpose of this study was to explore whether EA could ameliorate the dysregulation of pain sensation by suppressing microglial activation and the resulting neuroinflammatory response, and to evaluate whether this response was regulated by Toll-like receptor 4 (TLR4)/nuclear factor-kappa B(NF-κB) in the trigeminal nucleus caudalis (TNC) in a rat model of migraine. Methods: Repeated Inflammatory Soup (IS) was infused into the dura for seven sessions to establish a recurrent migraine-like rat model, and EA treatment was administered at Fengchi (GB20) and Yanglingquan (GB34) after daily IS infusion. Facial mechanical withdrawal thresholds were measured to evaluate the change in pain perception, and plasma samples and the TNC tissues of rats were collected to examine the changes in calcitonin gene-related peptide (CGRP), the Ibal-1-labelled microglial activation, and the resulting inflammatory response, including interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and their regulatory molecules TLR4/NF-κB, via enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and Western blot analysis. Results: Repeated IS injections into the dura induced facial mechanical paralgesia, which is the manifestation of migraine attacks, and increased the expression of CGRP, Ibal-1, microglial mediated inflammatory cytokines (IL-1β, TNF-α, IL-6), and regulatory molecules TLR4/NF-κB. EA at GB20/34 significantly attenuated repetitive IS-induced pain hypersensitivity. This effect was consistent with decreased levels of CGRP and inflammatory cytokines in the plasma and the TNC via the inhibition of microglia activation, and this response may be regulated by TLR4/NF-κB. Conclusions: EA ameliorated paralgesia in repetitive IS-induced migraine-like rats, which was mainly mediated by a reduction in microglial activation and microglial-mediated inflammatory responses that could be regulated by TLR4/NF-κB.Keywords:migraine;electroacupuncture;paralgesia;microglia;inflammatory response
研究领域:
神经科学
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疼痛管理
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针灸
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炎症
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR NEUROSCIENCE
·
2025
·Vol. 76
·期 1
·4
·
IF 2.7
Wu Zhixuan,Wang Dianyi,Yao Jing,Zhang Yue,Liu Jiayu
Background Migraine is a complex neurological disorder. While acupuncture is effective in alleviating migraines, its molecular mechanisms remain unclear. This study aims to explore these mechanisms. Methods We used bioinformatics to identify differentially expressed microRNAs (miRNAs) in migraine patients after acupuncture. Subsequently, luciferase reporter assays were utilized to verify the interaction between miRNAs and their regulated target gene mRNAs. RT-qPCR and Western blot analyzed key miRNAs’ regulatory effects on target genes. We also employed Transwell migration assays and a nitroglycerin (NTG)-induced migraine mouse model to systematically evaluate acupuncture’s efficacy and mechanism. Results Bioinformatics analysis revealed a significant upregulation of Hsa-miR-550a-3-5p in the peripheral blood of migraine patients after acupuncture treatment. Hsa-miR-550a-3-5p could directly inhibit the mRNA and protein expression of platelet and endothelial cell adhesion molecule 1 (PECAM1), reducing nitroglycerin-induced human brain microvascular endothelial cells (HBMECs). Following the downregulation of PECAM1 by hsa-miR-550a-3-5p, the transendothelial migration capacity of monocytes-macrophages was significantly reduced, and reducing the secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. Furthermore, it alleviates inflammation by regulating M2 macrophage polarization. In NTG-induced mice, acupuncture relieved migraine-like behaviors, an effect abolished by a miR-550a-3-5p inhibitor. Conclusion This study is the first to reveal that after acupuncture treatment, hsa-miR-550a-3-5p can be upregulated to target and inhibit PECAM1, reducing the transendothelial migration of inflammatory cells and the release of inflammatory cytokines, thereby alleviating migraine symptoms. This discovery provides scientific evidence for the efficacy of acupuncture and offers a new target for developing miRNA-based precision treatment strategies.
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DOI
PubMed
高影响因子
Pharmaceuticals
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2025
·Vol. 18
·期 3
·426
·
IF 4.8
Zhimin Song,Meijing Li,Ziwei Zhou,Xiaomeng Guo,Qi Wang,Zekuan Zhang,Keshu Wang,Qixiang Zheng,Wenjing Gou,Sha Wu,Hui Zhao,Muxin Gong
Background:Chronic migraine (CM) is a common complex nervous system disease, often accompanied by symptoms of the digestive tract that interact with each other, leading to prolonged and difficult-to-cure migraines. These symptoms are associated with abnormalities in 5-HT and its receptors. Wuzhuyu decoction (WZYD) is a traditional Chinese medicine prescription commonly used in clinics to treat CM; it relieves gastrointestinal symptoms, such as nausea and vomiting; however, its mechanism is still unclear. Investigating the differences in the role of WZYD compared to existing drugs targeting 5-HT receptors in the treatment of CM not only helps elucidate its pathogenesis but also provides possibilities for the development of new therapeutic approaches.Methods:An inflammation soup (IS)-induced CM male rat model was established. Based on a preliminary experiment, the target of WZYD in treating CM was determined by network pharmacology, and verified by molecular docking. ELISA, immunofluorescence, western blot, and real-time quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the expression levels of CM-related indicators (5-HT, calcitonin gene-related peptide (CGRP), and c-Fos) to ensure the successful establishment of the CM model and the effectiveness of the drug. On this basis, the protein expression levels of 5-HT1A/3A receptors and their cAMP-response element binding protein (CREB) signaling pathway were detected by western blot and immunohistochemistry. The role of 5-HT1A/3A receptors in the treatment of CM by WZYD was validated using a 5-HT1A receptor antagonist (WAY 100635) and a 5-HT3A receptor agonist (SR 57227).Results:The results showed that WZYD increased the expression of 5-HT in the brain, decreased the expression of CGRP, c-Fos, ionized calcium-binding adapter molecule 1 (Iba1), and relieved CM. At the same time, WZYD also increased the expression of the 5-HT1A receptor and decreased the expression of the 5-HT3A receptor in the brain and colon of CM rats. Subsequently, WZYD further exerted its brain-gut integrated therapeutic effects by regulating the CREB signaling pathway mediated by 5-HT1A/3A receptors in the brain and colon of CM rats.Conclusions:WZYD not only regulates neurotransmitters in the brain and colon at the same time, but also specifically regulates 5-HT1A/3A receptors in the brain and colon, which explains the characteristics and advantages of WZYD from a new perspective. While effectively relieving headache symptoms, it also improves related gastrointestinal symptoms, which is more conducive to the treatment of CM.
研究领域:
神经科学
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药理学
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中医药学
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产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2019
·Vol. 44
·期 7
·3078-3086
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IF 3.069
Shiyu Li,Zhongying Zhang,Jingdong Peng,Xiang Wang,Dengying Long,Hong Xian,Ranxi Ni,Huanjun Peng,Jun Chen
For the first time, a highly sensitive and selective detection technology of high-performance liquid chromatography associated with resonance Rayleigh scattering spectra (HPLC-RRS) is applied to analyze migraine drugs including zolmitriptan (ZON) and rizatriptan (RIN). In an HAc–NaAc buffer solution (pH = 4.5), ZON and palladium(II) chelate to form a chelating cation, namely, [Pd·ZON]2+, and then react with Erythrosin B (Ery) via electrostatic attractions and hydrophobicity to form a ternary complex, [Pd·ZON]·Ery2, resulting in a significantly enhanced RRS signal. The RRS signal was detected at the synchronous model. The calibration curves of ZON and RIN were linear in the range from 0.027 to 25 μg mL−1, and the detection limits (S/N = 3) were 9.70 ng mL−1 and 4.76 ng mL−1, respectively. In addition, the HPLC-RRS method showed that the recovery of the two migraine drugs was 98.90% to 100.87% and the RSD (n = 6) was 1.67% to 4.86%. In this study, the experiment conditions were optimized, and the reaction mechanism and reason for increment in RRS were studied. In human urine samples, the established method was applied for the synchronous detection of two antimigraine drugs with satisfactory results.
研究领域:
分析化学
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药物分析
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光谱学
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产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Chao Ma,Chunran Zhu,Yajun Zhang,Mei Yu,Yizhi Song,Yulong Chong,Yan Yang,Chan Zhu,Yucui Jiang,Changming Wang,Shuo Cheng,Keke Jia,Guang Yu,Jia Li,Zongxiang Tang
Background Increasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. Purpose Our work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. Methods/results After being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca 2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca 2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. Conclusion This work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.
研究领域:
神经科学
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药理学
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代谢
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HEADACHE AND PAIN
·
2022
·Vol. 23
·期 1
·1-14
·
IF 8.588
Pan Qi,Wang Yunfeng,Tian Ruimin,Wen Qianwen,Qin Guangcheng,Zhang Dunke,Chen Lixue,Zhang Yixin,Zhou Jiying
Background Central sensitization is an important pathophysiological mechanism of chronic migraine (CM), and microglia activation in trigeminocervical complex (TCC) contributes to the development of central sensitization. Emerging evidence implicates that blocking sphingosine-1-phosphate receptor 1 (S1PR1) can relieve the development of chronic pain and inhibit the activation of microglia. However, it is unclear whether S1PR1 is involved in the central sensitization of CM. Therefore, the purpose of this study is to explore the role of S1PR1 and its downstream signal transducers and activators of transcription 3 (STAT3) signaling pathway in the CM, mainly in inflammation.Methods Chronic intermittent intraperitoneal injection of nitroglycerin (NTG) established a mouse model of CM. First, we observed the changes and subcellular localization of S1PR1 in the trigeminocervical complex (TCC). Then, W146, a S1PR1 antagonist; SEW2871, a S1PR1 agonist; AG490, a STAT3 inhibitor were applied by intraperitoneal injection to investigate the related molecular mechanism. The changes in the number of microglia and the expression of calcitonin gene-related peptide (CGRP) and c-fos in the TCC site were explored by immunofluorescence. In addition, we studied the effect of S1PR1 inhibitors on STAT3 in lipopolysaccharide-treated BV-2 microglia.Results Our results showed that the expression of S1PR1 was increased after NTG injection and S1PR1 was colocalized with in neurons and glial cells in the TCC. The S1PR1 antagonist W146 alleviated NTG-induced hyperalgesia and suppressed the upregulation of CGRP, c-fos and pSTAT3 in the TCC. Importantly, blocking S1PR1 reduced activation of microglia. In addition, we found that inhibiting STAT3 signal also attenuated NTG-induced basal mechanical and thermal hyperalgesia.Conclusion sOur results indicate that inhibiting S1PR1 signal could alleviate central sensitization and inhibit microglia activity caused by chronic NTG administration via STAT3 signal pathway, which provide a new clue for the clinical treatment of CM.
研究领域:
神经科学
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药理学
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疼痛研究
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Xiaohui Zhang,Yule Wang,Kai Zhang,Hongda Sheng,Yuhan Wu,Huimin Wu,Yingchao Wang,Jianli Guan,Qingfen Meng,Huahuan Li,Zhenhao Li,Guanwei Fan,Yi Wang
Background Migraine is the third most common disease worldwide, leading to severely decreased quality of life for the patients. In spite of great efforts endeavored in pharmacological and nonpharmacological therapeutic strategies for treating migraine, the outcome is rather disappointing in terms of efficacy. Compelling evidence shows that the expression level of dopamine receptor D2 (DRD2) plays an essential role in progression of migraine. Purpose To explore potential therapeutical possibilities, the attention was paid to Yuanhu Zhitong formula (YHZTF), which is a classical traditional Chinese medicine prescription frequently applied to relieve pain. The aim of this study was to identify the promising compounds derived from YHZTF with anti-migraine effects and investigate the underlying molecular mechanism. Methods The high-resolution mass spectrometry and molecular networking were performed for comprehensive chemical profiling of YHZTF. Network pharmacology was used to generate herbal-component-target-pathway network. Based on the pathway enrichment analysis, the active substances of anti-migraine and the potential molecular mechanism were further determined by performing animal experiments combined with molecular docking strategy. Results In total, 31 substances were identified in YHZTF, including alkaloids such as tetrahydropalmatine and protopine . The analysis of herbal-component-target-pathway network suggests that the alkaloid substances (e.g. tetrahydropalmatine and protopine) from YHZTF target dopamine receptors , thus can be linked to neuroactive ligand-receptor interaction pathways. In a nitroglycerin-induced migraine animal model, pretreatment with tetrahydropalmatine or protopine substantially lessened the aberrant migraine-like symptoms. The results of molecular docking analysis showed that tetrahydropalmatine and protopine had strong affinities to dopamine receptor D2 (DRD2). Using RT-qPCR, the investigators found that DRD2 was significantly down-regulated at the mRNA level in brain tissues of tetrahydropalmatine and protopine-treated group compared to the control group. Conclusion Collectively, the results provide reliable evidence showing that the active substances tetrahydropalmatine and protopine from YHZTF lessens migraine symptoms in an in vivo mouse model suggestively via regulating expression of DRD2. These findings shed light on novel therapeutic strategies and targets to treat migraine using natural products.
研究领域:
药理学
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神经科学
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中医药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Yulong Chen,Qingzhou Cheng,Shan Zeng,Site Lv
Background: Migraine is a common neurovascular disorder with typical throbbing and unilateral headaches, causing a considerable healthcare burden on the global economy. This research aims to prepare chitosan-alginate (CS-AL) nanoparticles (NPs) containing Foshousan oil (FSSO) and investigate its potential therapeutic effects on the treatment of migraine. Methods: FSSO-loaded CS-AL NPs were prepared by using the single emulsion solvent evaporation method. Lipopolysaccharide (LPS)-stimulated BV-2 cells and nitroglycerin (NTG)-induced migraine mice were further used to explore anti-migraine activities and potential mechanisms of this botanical drug. Results: FSSO-loaded CS-AL NPs (212.1 ± 5.2 nm, 45.1 ± 6.2 mV) had a well-defined spherical shape with prolonged drug release and good storage within 4 weeks. FSSO and FSSO-loaded CS-AL NPs (5, 10, and 15 μg/mL) showed anti-inflammatory activities in LPS-treated BV-2 cells via reducing the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO), but elevating interleukin-10 (IL-10) expressions. Moreover, FSSO-loaded CS-AL NPs (52 and 104 mg/kg) raised pain thresholds against the hot stimulus and decreased acetic acid-induced writhing frequency and foot-licking duration in NTG-induced migraine mice. Compared with the model group, calcitonin gene-related peptide (CGRP) and NO levels were downregulated, but 5-hydroxytryptamine (5-HT) and endothelin (ET) levels were upregulated along with rebalanced ET/NO ratio, and vasomotor dysfunction was alleviated by promoting cerebral blood flow (CBF) in the FSSO-loaded CS-AL NPs (104 mg/kg) group. Conclusion: FSSO-loaded CS-AL NPs could attenuate migraine via inhibiting neuroinflammation in LPS-stimulated BV-2 cells and regulating vasoactive substances in NTG-induced migraine mice. These findings suggest that the FSS formula may be exploited as new phytotherapy for treating migraine.
研究领域:
药理学
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纳米技术
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神经科学
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植物药
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Lingxian Liu,Haibo Li,Zhenzhong Wang,Xinsheng Yao,Wei Xiao,Yang Yu
ABSTRACT Background Migraine is widely recognized as the third most prevalent medical condition globally. Tianshu capsule (TSC), derived from “Da Chuan Xiong Fang” of the Jin dynasty, is integral in the clinical treatment of migraines. However, the chemical properties and therapeutic mechanisms of TSC different portions remain unclear. Purpose This study was designed to investigate the effects of TSC different portions (including small molecular TSCP-SM and polysaccharides TSC-P) on migraines and explore the underlying mechanisms. Study design and methods First of all, migraine rats were established by nitroglycerin injection and treated with TSC, TSC-P, and TSC-SM. ELISA, qPCR, and immunofluorescence were used to evaluate the pharmacological effects on migraine rats. Secondly, UPLC-Q/TOF-MS and GC-MS were employed to detect the components of TSCP-SM. PMP-HPLC, NMR, FT-IR, UV-Vis, AFM, and SEM were used for the chemical profiling of polysaccharides. Thirdly, the metabolic behavior profile of TSC-P was characterized by oral administrated fluorescence-labeled TSC-P and detected by NIR imaging. Finally, the anti-migraine mechanisms were explored by determining the composition of gut microbiota, analyzing colonic short-chain fatty acids (SCFAs), and examining serum tryptophan-related metabolites. Results Both small molecules (45 volatiles and 114 small molecules) and polysaccharides (including Glc, Ara, Gal, and Gal A) have exhibited effectiveness in alleviating migraines, and this efficacy is associated with reduced CGRP and iNOS levels, along with increased β -EP expressions. Further mechanistic exploration revealed that small-molecules exhibited effectiveness in migraines treatment by exerting antioxidative actions, while polysaccharides demonstrated superior therapeutic effects in regulating 5-HT levels. By monitoring the metabolic behavior of polysaccharides with fluorescent labeling, it was observed that TSC-P exhibited poor absorption. Instead, TSC-P demonstrated its therapeutic effects by modulating the aberrations in gut microbiota (including Alloprevotella, Muribaculaceae_ge , and Ruminococcaceae_UCG-005 ), cecum short-chain fatty acids (such as isobutyric, isovaleric, and valeric acids), and serum tryptophan-related metabolites (including indole-3-acetamide, tryptophol, and indole-3-propionic acid). Conclusion This research provides innovative insights into chemical composition, metabolic behavior, and proposed anti-migraine mechanisms of TSC from a polarity-based perspective, and pioneering an exploration focused on the polysaccharide components within TSC for the first time.
研究领域:
药理学
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神经科学
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分析化学
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代谢组学
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微生物学
✓ 已验证
DOI
PubMed
高影响因子
Molecular Pain
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2024
·
IF 2.8
Min Zhou,Fang Pang,Dongmei Liao,Yunhao Yang,Ying Wang,Zhuxin Yang,Xinlu He,Chenglin Tang
Background: Recent studies have demonstrated that activated microglia were involved in the pathogenesis of central sensitization characterized by cutaneous allodynia in migraine. Activation of microglia is accompanied by increased expression of its receptors and release of inflammatory mediators. Acupuncture and its developed electroacupuncture (EA) have been recommended as an alternative therapy for migraine and are widely used for relieving migraine-associated pain. However, it remains rare studies that show whether EA exerts anti-migraine effects via inhibiting microglial activation related to a release of microglial receptors and the inflammatory pathway. Therefore, this study aimed to investigate EA’ ability to ameliorate central sensitization via modulation of microglial activation, microglial receptor, and inflammatory response using a rat model of migraine induced by repeated epidural chemical stimulation. Methods: In the present study, a rat model of migraine was established by epidural repeated inflammatory soup (IS) stimulation and treated with EA at Fengchi (GB20) and Yanglingquan (GB34) and acupuncture at sham-acupoints. Pain hypersensitivity was further determined by measuring the mechanical withdrawal threshold using the von-Frey filament. The changes in c-Fos and ionized calcium binding adaptor molecule 1 (Ibal-1) labeled microglia in the trigeminal nucleus caudalis (TNC) were examined by immunflurescence to assess the central sensitization and whether accompanied with microglia activation. In addition, the expression of Ibal-1, microglial purinoceptor P2X4, and its associated inflammatory signaling pathway mediators, including interleukin (IL)-1β, NOD-like receptor protein 3 (NLRP3), and Caspase-1 in the TNC were investigated by western blot and real-time polymerase chain reaction analysis. Results: Allodynia increased of c-Fos, and activated microglia were observed after repeated IS stimulation. EA alleviated the decrease in mechanical withdrawal thresholds, reduced the activation of c-Fos and microglia labeled with Ibal-1, downregulated the level of microglial purinoceptor P2X4, and limited the inflammatory response (NLRP3/Caspase-1/IL-1β signaling pathway) in the TNC of migraine rat model. Conclusions: Our results indicate that the anti-hyperalgesia effects of EA ameliorate central sensitization in IS-induced migraine by regulating microglial activation related to P2X4R and NLRP3/IL-1β inflammatory pathway.
研究领域:
神经科学
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疼痛管理
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针灸
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炎症
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小胶质细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
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2024
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IF 15.8
Guanlin Wang,Zizhao Zhai,Wenhao Wang,Xiao Xia,Haihua Guo,Xiao Yue,Xiaoyuan Wang,Bing Zhu,Zhengwei Huang,Xin Pan,Ying Huang,Chuanbin Wu,Xuejuan Zhang
The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood–brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery (R2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.
研究领域:
药学
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纳米技术
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神经科学
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药物递送系统
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药理学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）