RESUMEN
Neuroinflammation has been known as an important pathogenetic contributor of Alzheimer's disease (AD). Pterostilbene is a natural compound which has neuroprotective activity. However, the effect of pterostilbene on amyloid-ß (Aß)-induced neuroinflammation has not been clarified. The aim of the present study was to investigate the effect of pterostilbene on Aß-induced neuroinflammation in microglia. The results indicated that pterostilbene attenuated Aß1-42 -induced cytotoxicity of BV-2 cells. Aß1-42 induced NO production and iNOS mRNA and protein expression, while pterostilbene inhibited the induction. The expression and secretion levels of IL-6, IL-1ß, and TNF-α were enhanced by Aß1-42 treatment, whereas pterostilbene decreased them. Aß1-42 activated NLRP3/caspase-1 inflammasome, which was inactivated by pterostilbene. In addition, the inhibitor of caspase-1 Z-YVAD-FMK attenuated the Aß1-42 -induced neuroinflammation in BV-2 cells. In conclusion, pterostilbene attenuated the neuroinflammatory response induced by Aß1-42 in microglia through inhibiting the NLRP3/caspase-1 inflammasome pathway, indicating that pterostilbene might be an effective therapy for AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Caspasa 1/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fragmentos de Péptidos/metabolismo , Estilbenos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Animales , Caspasa 1/genética , Inhibidores de Caspasas/farmacología , Línea Celular Transformada , Inflamasomas/genética , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Ratones , Microglía , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fragmentos de Péptidos/genética , Clorometilcetona de Tosilfenilalanila/análogos & derivados , Clorometilcetona de Tosilfenilalanila/farmacologíaRESUMEN
There are several studies reporting that different plant-based metabolites are potential inhibitors of protein amyloid fibrillation. As chemical features of metabolites can regulate protein aggregation process, in the present in vitro investigation, tau protein was selected as a model of Alzheimer's disease to elaborate the inhibitory effect of syringic acid (SA) on its assembly and associated neurotoxicity in aggregation conditions. Extrinsic fluorescence, Congo red adsorption, and CD spectroscopic studies, TEM, size-exclusion chromatography, and MALDI-TOF mass spectrometry analysis along with MTT and qRT-PCR assays were performed to assess the inhibitory effects of SA against tau aggregation and neurotoxicity. It was shown that SA has the tendency to control the aggregation of the tau proteins through modulating the amyloid kinetic parameters, exposure of hydrophobic residues, and structural changes. Moreover, the structures formed in the presence of SA recovered the viability of neuron-like cells (SH-SY5Y) through regulation of endoplasmic reticulum stress signaling pathway by downregulation of ATF-6, caspase-8 and caspase-3 mRNA. In conclusion, it can be suggested that SA may be used as a potential small molecule in the development of therapeutic platforms against Alzheimer's disease.