Electroacupuncture Inhibits NLRP3-Mediated Microglial Pyroptosis to Ameliorate Chronic Neuropathic Pain in Rats

Journal of Pain Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 1115 - 1129

Published: March 1, 2025

Patients with neuropathic pain (NP), caused by injury or disease of the somatosensory nervous system, usually suffer from severe pain. Our previous studies revealed that electroacupuncture (EA) stimulation could effectively improve NP. However, underlying mechanisms EA have not been fully clarified. This study aimed to investigate specific in alleviating NP, focusing on pyroptosis. Chronic Constriction Injury (CCI) model was established male Sprague-Dawley rats. CCI rats were treated at acupoints GV20 and ST36 or/with NOD-like receptor protein 3 (NLRP3) antagonist MCC950. treatment administered for successive 14 days 7 after surgery. The mechanical withdrawal threshold (MWT) paw latency (PWL) performed during experiment. At end experiment, spinal cord segments serum collected, ELISA detected expression inflammatory factors, immunofluorescence microglia neuron cells pyroptosis biomarkers, Western blot NLRP3 pathway. significantly alleviated hypersensitivity increasing MWT PWL. Moreover, reduced levels pro-inflammatory cytokines IL-1β TNF-α tissue. Mechanistically, pyroptosis-related proteins, including NLRP3, N-GSDMD, Cleaved Caspase-1, IL-18 as well downregulated EA, indicating attenuated phenotype NP In particular, co-expression Caspase-1 N-GSDMD rather than neuronal astrocytic within Pharmacological inhibition inflammasome MCC950 alleviates CCI-induced while blocking EA's effect anti-pyroptosis These findings demonstrate ameliorates neuroinflammation relieve chronic suppressing activation microglia. may serve a viable therapy

Language: Английский

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Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway

eNeuro, Journal Year: 2025, Volume and Issue: 12(3), P. ENEURO.0329 - 24.2025

Published: March 1, 2025

Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is mitigating pain-sensitive symptoms BPS/IC and the mechanisms involved. This study aims investigate analgesic effect mechanism therapy. To achieve this goal, we employed several techniques: mechanical threshold tests assess sensitivity, urodynamic studies evaluate function, Western blotting (WB) for protein analysis, immunofluorescence visualizing, transcriptomics. A rat model was established through systemic intraperitoneal injection with cyclophosphamide (CYP). executed by stimulating deep part hypochondriac point, where 2nd-4th sacral nerves traverse. treatment observed effectively reduce allodynia, enhance urinary suppress activation microglial cells, alleviate neuroinflammation. Additionally, demonstrated capability downregulate BDNF-TrkB signal transduction spinal dorsal horn. Transcriptome sequencing indicated that potentially inhibits excitatory neural transmission modulates pathways related longevity. Furthermore, shown efficacy treating conditions such Huntington's disease, amyotrophic lateral sclerosis, prion diseases. In conclusion, regulating signaling, can dysfunction allodynia cyclophosphamide-induced model. Our research elucidates underlying offers new theoretical insights addressing painful BPS.Significance Statement major factor (BPS/IC), making management crucial. explores potential electroacupuncture therapeutic approach improve function induced cyclophosphamide. findings demonstrate significantly reduces enhances decreases neuroinflammation modulating signaling The highlights EA's inhibit provide relief conditions. These results offer into therapy, improving strategies similar syndromes.

Language: Английский

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Neuroprotective role of geniposide-loaded UMSC nanovesicles in depression via P2ry12 downregulation

Phytomedicine, Journal Year: 2025, Volume and Issue: 140, P. 156581 - 156581

Published: March 13, 2025

Language: Английский

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TRPC3 contributes to cyclophosphamide-induced cystitis progression by enhancing bladder fibrosis through activation of the TGF-β/smad pathway

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 9, 2025

Bladder pain syndrome/Interstitial cystitis (BPS/IC) is a chronic urological disorder affecting 2.7%-6.5% of the population. The condition characterized by significant bladder-related pain, with approximately 50% IC/BPS patients exhibiting bladder fibrosis. Transient receptor potential cation channel subfamily C member 3 (TRPC3), protein linked to fibrosis in heart and kidneys, emerged as therapeutic target for this condition. Using cyclophosphamide-induced rat model, we employed RNA sequencing transcriptional profiling, Western blot quantification, Masson staining fibrotic assessment. Cellular-specific TRPC3 expression patterns were elucidated through single-cell transcriptomic analysis. inhibition was implemented via intraperitoneal administration Pyrazole 3. study assessed mechanical sensitivity function von Frey testing cystometry. Significant findings revealed markedly upregulated rats. substantially improved reduced micturition frequency. predominantly expressed fibroblasts fibrosis-related pathways are increased markers collagen fiber deposition both reversed inhibition. And TGF-β/Smad signaling pathway notably activated subsequently downregulated activation contributes significantly IC/BPS. Inhibiting ameliorates symptoms modulating pathway, suggesting it promising managing challenging limited current treatment options.

Language: Английский

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The NLRP3 Inflammasome Inhibitor Dapansutrile Attenuates Cyclophosphamide-Induced Interstitial Cystitis

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: June 3, 2022

Interstitial cystitis (IC)/bladder pain syndrome (BPS), hereafter referred together as IC, is a clinical characterized by sterile inflammation in the bladder. While etiology and pathophysiology of IC remain unclear, it may involve autoimmunity light significant role played NLRP3 inflammasome. However, effect inhibitors including dapansutrile (Dap) on had not been explored previously. Here, we investigated Dap cyclophosphamide (CYP)-induced experimental mouse model which results functional histological alterations confined to urinary bladder (UB) comparable that IC. CYP-induced mice treated with exhibited improved UB pathology reductions scores frequency number mast cells neutrophils, relative received CYP alone. Dap- CYP-treated also infiltration T spleen iliac lymph nodes (ILNs) concurrent decrease (p<0.01) CXCR3 + CD8 UB, induction systemic mucosal dendritic (DCs), reduced levels proinflammatory cytokines, compared We observed decreases expression several signaling pathways regulators, interleukin-1 beta (IL-1β), NLRP3, caspase-1, nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS) CYP- Dap-treated mice, those receiving Taken together, these suggest suppresses through reduction cells, neutrophils induces DCs protective measure. The present study identifies mechanisms underlying amelioration inhibitor provide an avenue for potential therapeutic agent treatment

Language: Английский

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Broaden Horizons: The Advancement of Interstitial Cystitis/Bladder Pain Syndrome

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 14594 - 14594

Published: Nov. 23, 2022

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating disease that induces mental stress, lower urinary symptoms, and pelvic pain, therefore resulting in decline quality of life. The present diagnoses treatments still lead to unsatisfactory outcomes, novel diagnostic therapeutic modalities are needed. Although our understanding the etiology pathophysiology IC/BPS growing, altered permeability impaired urothelium, sensitized nerves on bladder wall, chronic or intermittent sensory with inaccurate location, as well pathologic angiogenesis, fibrosis, Hunner lesions, all act barriers better treatments. This study aimed summarize comprehensive information research, thereby promoting progress aspects diagnosis, treatment, prognosis. According diverse international guidelines, associated multiple factors, while presence lesions could largely distinguish pathology, treatment non-Hunner patients. On basis diagnosis exclusion, procedures undergoing transition from single approach multimodal strategies targeting different potential phenotypes recommended by guidelines. Investigations into mechanisms involved sensation, fibrosis indicate for further strategies, both treatment. An overview terms epidemiology, etiology, fundamental research provided latest evidence. shared decision-making, strategy individual patients would be great benefit entire process management. complexity emerging evidence elicit more relevant studies optimize management

Language: Английский

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Mechanism of NLRP3 inflammasome intervention for synovitis in knee osteoarthritis: A review of TCM intervention

Frontiers in Genetics, Journal Year: 2023, Volume and Issue: 14

Published: March 29, 2023

Objective: This paper briefly reviews the structure and function of NLRP3 inflammasomes, signaling pathway, relationship with synovitis in KOA, intervention traditional Chinese medicine (TCM) inflammasomes as a means to improve its therapeutic potential clinical application. Method: Literatures about KOA were reviewed analyze discuss. Result: inflammasome can activate NF-κB mediated signal transduction, which turn causes expression proinflammatory cytokines, initiates innate immune response, triggers KOA. The TCM monomer/active ingredient, decoction, external ointment, acupuncture regulating are helpful alleviate Conclusion: plays significant role pathogenesis targeting be novel approach direction for treatment

Language: Английский

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Amygdala-Targeted Relief of Neuropathic Pain: Efficacy of Repetitive Transcranial Magnetic Stimulation in NLRP3 Pathway Suppression

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: April 4, 2024

Abstract This study investigates the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a nonpharmacological approach to treating neuropathic pain (NP), major challenge in clinical research. Conducted on male Sprague-Dawley rats with NP induced through chronic constriction injury sciatic nerve, research assessed behaviors and impact rTMS molecular interactions within amygdala. Through comprehensive analysis involving Mechanical Withdrawal Threshold (MWT), Thermal Latency (TWL), RNA transcriptome sequencing, RT-qPCR, Western blotting, immunofluorescence staining, Co-Immunoprecipitation (Co-IP), focused expression interaction integrin αvβ3 its receptor P2X7R. Findings reveal that significantly influences models, suggesting an inhibition NP-associated NLRP3 inflammatory pathway disruption αvβ3-P2X7R interactions. These outcomes highlight potential alleviating by targeting amygdala, offering promising therapeutic avenue for managing NP.

Language: Английский

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Intrathecal umbilical cord mesenchymal stem cells injection alleviates neuroinflammation and oxidative stress in the cyclophosphamide-induced interstitial cystitis rats through the Sirt1/Nrf2/HO-1 pathway

Life Sciences, Journal Year: 2023, Volume and Issue: 331, P. 122045 - 122045

Published: Aug. 25, 2023

Language: Английский

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Repeated closed-head mild traumatic brain injury-induced inflammation is associated with nociceptive sensitization

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Aug. 27, 2023

Abstract Background Individuals who have experienced mild traumatic brain injuries (mTBIs) suffer from several comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated pain, role inflammation in long-term pain after mTBIs is not fully elucidated. Given shifting dynamics inflammation, it important to understand spatial-longitudinal changes inflammatory processes following and their effects on TBI-related Methods We utilized a recently developed transgenic caspase-1 luciferase reporter mouse model monitor activation through thinned skull window vivo setting three closed-head mTBI events. Organotypic coronal slice cultures acutely dissociated dorsal root ganglion (DRG) cells provided tissue-relevant context signal. Mechanical allodynia was assessed by mechanical withdrawal threshold von Frey thermal hyperalgesia latency radiant heat. Mouse grimace scale (MGS) used detect spontaneous or non-evoked In some experiments, mice were prophylactically treated with MCC950, potent small molecule inhibitor NLRP3 inflammasome assembly inhibit injury-induced signaling. Bioluminescence spatiotemporal quantified head hind paws, confirmed immunoblot. Immunofluorescence staining progression astrogliosis microglial ex tissue repetitive mTBIs. Results Mice exhibited significant increases bioluminescence signals within paws for at least one week each injury. Consistently, immunoblotting immunofluorescence experiments that led activation, astrogliosis, microgliosis. Persistent MGS paw thresholds, indicative states, observed post-injury same animals vivo. also enhanced responses preparations DRG 3 days treatment MCC950 significantly reduced activation-associated bioluminescent decreased stimulus-evoked non-stimulus evoked nociception. Conclusions Our findings suggest states peripheral nervous system repeated are coincidental development nociceptive sensitization, these events can be inhibition activation.

Language: Английский

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