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1.
World J Psychiatry ; 14(8): 1254-1266, 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39165552

RESUMEN

BACKGROUND: Neuropathic pain (NP) is the primary symptom of various neurological conditions. Patients with NP often experience mood disorders, particularly depression and anxiety, that can severely affect their normal lives. Microglial cells are associated with NP. Excessive inflammatory responses, especially the secretion of large amounts of pro-inflammatory cytokines, ultimately lead to neuroinflammation. Microglial pyroptosis is a newly discovered form of inflammatory cell death associated with immune responses and inflammation-related diseases of the central nervous system. AIM: To investigate the effects of botulinum toxin type A (BTX-A) on microglial pyroptosis in terms of NP and associated mechanisms. METHODS: Two models, an in vitro lipopolysaccharide (LPS)-stimulated microglial cell model and a selective nerve injury model using BTX-A and SPP1 knockdown treatments, were used. Key proteins in the pyroptosis signaling pathway, NLRP3-GSDMD, were assessed using western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence. Inflammatory factors [interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α] were assessed using enzyme-linked immunosorbent assay. We also evaluated microglial cell proliferation and apoptosis. Furthermore, we measured pain sensation by assessing the delayed hind paw withdrawal latency using thermal stimulation. RESULTS: The expression levels of ACS and GSDMD-N and the mRNA expression of TNF-α, IL-6, and IL-1ß were enhanced in LPS-treated microglia. Furthermore, SPP1 expression was also induced in LPS-treated microglia. Notably, BTX-A inhibited SPP1 mRNA and protein expression in the LPS-treated microglia. Additionally, depletion of SPP1 or BTX-A inhibited cell viability and induced apoptosis in LPS-treated microglia, whereas co-treatment with BTX-A enhanced the effect of SPP1 short hairpin (sh)RNA in LPS-treated microglia. Finally, SPP1 depletion or BTX-A treatment reduced the levels of GSDMD-N, NLPRP3, and ASC and suppressed the production of inflammatory factors. CONCLUSION: Notably, BTX-A therapy and SPP1 shRNA enhance microglial proliferation and apoptosis and inhibit microglial death. It improves pain perception and inhibits microglial activation in rats with selective nerve pain.

2.
J Pain ; 24(5): 901-917, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36646400

RESUMEN

Administration of cisplatin and other chemotherapy drugs is crucial for treating tumors. However, cisplatin-induced pain hypersensitivity is still a critical clinical issue, and the underlying molecular mechanisms have remained unresolved to date. In this study, we found that repeated cisplatin treatments remarkedly upregulated the P2Y12 expression in the spinal cord. Expression of P2Y12 was predominant in the microglia. Pharmacological inhibition of P2Y12 expression markedly attenuated the cisplatin-induced pain hypersensitivity. Meanwhile, blocking the P2Y12 signal also suppressed cisplatin-induced microglia hyperactivity. Furthermore, the microglia Src family kinase/p38 pathway is required for P2Y12-mediated cisplatin-induced pain hypersensitivity via the proinflammatory cytokine IL-18 production in the spinal cord. Blocking the P2Y12/IL-18 signaling pathway reversed cisplatin-induced pain hypersensitivity, as well as activation of N-methyl-D-aspartate receptor and subsequent Ca2+-dependent signals. Collectively, our data suggest that microglia P2Y12-SFK-p38 signaling contributes to cisplatin-induced pain hypersensitivity via IL-18-mediated central sensitization in the spinal, and P2Y12 could be a potential target for intervention to prevent chemotherapy-induced pain hypersensitivity. PERSPECTIVE: Our work identified that P2Y12/IL-18 played a critical role in cisplatin-induced pain hypersensitivity. This work suggests that P2Y12/IL-18 signaling may be a useful strategy for the treatment of chemotherapy-induced pain hypersensitivity.


Asunto(s)
Antineoplásicos , Microglía , Humanos , Microglía/metabolismo , Cisplatino/toxicidad , Interleucina-18/metabolismo , Sensibilización del Sistema Nervioso Central , Hiperalgesia/metabolismo , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dolor/metabolismo , Médula Espinal/metabolismo , Transducción de Señal/fisiología , Antineoplásicos/efectos adversos
3.
Mol Pain ; 18: 17448069221075891, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35083936

RESUMEN

Tumor metastasis to bone is often accompanied by a severe pain syndrome (cancer-induced bone pain, CIBP) that is frequently unresponsive to analgesics, which markedly reduces patient quality of life and cancer treatment tolerance in patients. Prolonged pain can induce hypersensitivity via spinal plasticity, and several recent studies have implicated the involvement of vascular endothelial growth factor-A (VEGF-A) signaling in this process. Here, we speculated that CIBP is associated with VEGF-A/VEGFR2 signaling in the spinal cord. A mouse model of CIBP was established by intramedullary injection of Lewis lung carcinoma (LLC) cells in the mouse femur. Pain sensitization and potential amelioration via VEGF-A/VEGFR2 blockade were measured using paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to thermal. Spinal VEGF-A/VEGFR2 signaling was blocked by intrathecal injection of the VEGF-A antibody or the specific VEGFR2 inhibitor ZM323881. Changes in the expression levels of VEGF-A, VEGFR2, and other pain-related signaling factors were measured using western blotting and immunofluorescence staining. Mice after LLC injection demonstrated mechanical allodynia and thermal hyperalgesia, both of which were suppressed via anti-VEGF-A antibody or ZM323881. Conversely, the intrathecal injection of exogenous VEGF-A was sufficient to cause pain hypersensitivity in naïve mice via the VEGFR2-mediated activation of protein kinase C. Moreover, the spinal blockade of VEGF-A or VEGFR2 also suppressed N-methyl-D-aspartate receptor (NMDAR) activation and downstream Ca2+-dependent signaling. Thus, spinal VEGF-A/VEGFR2/NMDAR signaling pathways may be critical mediators of CIBP.


Asunto(s)
Neoplasias Óseas , Dolor en Cáncer , Animales , Neoplasias Óseas/metabolismo , Dolor en Cáncer/patología , Carcinoma Pulmonar de Lewis , Ratones , Neuronas/metabolismo , Dolor/metabolismo , Calidad de Vida , Factor A de Crecimiento Endotelial Vascular
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