RESUMEN
Daphnetin (7, 8-dihydroxycoumarin, DAPH), a coumarin derivative isolated from Daphne odora var., recently draws much more attention as a promising drug candidate to treat neuroinflammatory diseases due to its protective effects against neuroinflammation. However, itscontribution to chronic inflammatory pain is largely unknown. In the current work, we investigated the effects of DAPH in a murine model of inflammatory pain induced by complete Freund's adjuvant (CFA) and its possible underlying mechanisms. Our results showed that DAPH treatment significantly attenuated mechanical allodynia provoked by CFA. A profound inhibition of spinal glial activation, followed by attenuated expression levels of spinal pro-inflammatory cytokines, was observed in DAPH-treated inflammatory pain mice. Further study demonstrated that DAPH mediated negative regulation of spinal NF-κB pathway, as well as its preferential activation of Nrf2/HO-1 signaling pathway in inflammatory pain mice. This study, for the first time, indicated that DAPH might preventthe development of mechanical allodynia in mice with inflammatory pain. And more importantly, these data provide evidence for the potential application of DAPH in the treatment of chronic inflammatory pain.
Asunto(s)
Dolor Crónico/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Umbeliferonas/farmacología , Animales , Dolor Crónico/inmunología , Dolor Crónico/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Adyuvante de Freund/administración & dosificación , Adyuvante de Freund/inmunología , Hemo-Oxigenasa 1/metabolismo , Humanos , Hiperalgesia/inmunología , Hiperalgesia/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/inmunología , Neuroglía/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Dolor/inmunología , Dolor/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patología , Umbeliferonas/uso terapéuticoRESUMEN
Protein arginine methyltransferase 5 (PRMT5), a type II PRMT enzyme, is reported as an important therapeutic target in leukemia and lymphoma. In the present study, based on the combination of virtual screening and biochemical validations, we discovered a series of small-molecule inhibitors targeting PRMT5. Among those, DC_Y134 exhibited the most potent activity with IC50 value of 1.7 µM and displayed good selectivity against other methyltransferases. Further treatment with DC_Y134 inhibited the proliferation of several hematological malignancy cell lines by causing cell cycle arrest and apoptosis. Western blot assays indicated that DC_Y134 reduced the cellular symmetrically dimethylated levels. In addition, we analyzed the binding mode of DC_Y134 through molecular docking, which revealed that DC_Y134 occupies the binding site of substrate arginine and explained the selectivity of this inhibitor. Taken together, compound DC_Y134 could be used to elucidate the biological roles of PRMT5 and serve as a lead compound for treatment of hematologic malignancies.