RESUMEN
Andrographolide (Andro), a labdane diterpene, possesses anti-inflammatory properties and has been used to treat numerous inflammatory diseases. Novel findings revealed that Andro might be vital in regulating pain. However, the contribution of Andro to chronic inflammatory pain has yet to be determined, and its underlying mechanism of action remains unknown. In this study, we observed that Andro attenuated mechanical allodynia in inflammatory pain mice induced by injecting complete Freund's adjuvant (CFA) into the right hind paws. This analgesic effect of Andro is mainly dependent on its inhibition of microglial overactivation and the release of proinflammatory cytokines (TNF and IL-1ß) in lumbar spinal cords of inflammatory pain model mice. More importantly, our data in vivo and in vitro revealed a negative role for Andro in regulating the TLR4/NF-κB signaling pathway, which might contribute to the inhibition of spinal microglial activation and proinflammatory cytokines production, and the improvement of paw withdrawal thresholds in a mouse model of chronic inflammatory pain evoked by CFA. We further found the potential interaction of Andro with TLR4/myeloid differentiation factor 2 heterodimer using molecular modeling, implying that TLR4 might be a potential target for Andro to exert an analgesic effect. Taken together, our findings demonstrated that the modulation of spinal microglial activation by Andro might be substantially conducive to managing chronic pain triggered by neuroinflammation.
Asunto(s)
Diterpenos , Hiperalgesia , Ratones , Animales , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Microglía/metabolismo , Inflamación/metabolismo , Receptor Toll-Like 4/metabolismo , Dolor/tratamiento farmacológico , Dolor/metabolismo , Diterpenos/farmacología , Diterpenos/uso terapéutico , Diterpenos/metabolismo , Citocinas/metabolismo , Médula Espinal , Analgésicos/farmacología , Analgésicos/uso terapéuticoRESUMEN
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.