RESUMEN
The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPß and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs.
RESUMEN
Astragalin (AST) is a natural flavonoid with excellent antioxidant and anti-inflammatory activities. However, whether AST is an effective chemical for neuronal protection and its underlying mechanisms remain to be elucidated. In this study, we established a mouse model of cognitive impairment and aging-like phenotype induced by sequential administration of AlCl3 and D-galactose (Gal). We found that AST effectively ameliorated cognitive impairment in the model mice and improved their learning and memory performance in the Morris water maze (MWM) test. AlCl3/Gal-induced activation of astrocytes and microglia and inflammation were observed by immunohistochemistry and immunofluorescence, but could be attenuated by AST. In addition, alterations in oxidative stress-regulating enzymes or markers, including T-SOD, T-AOC, CAT, GSH-Px, and MDA, as well as the pro-inflammatory factors TNF-α, IL-1ß, and IL-6, were restored. At the mechanistic level, AlCl3/Gal-intoxicated mice showed a significant elevation of Notch/HES-1 and NF-κB signaling axis corresponding to microglia activation and inflammation. AST attenuated the activation of Notch/HES-1 and NF-κB signaling axis, thus reducing the inflammation. In summary, AST is a promising natural product to protect neurons from toxin-induced injury, indicating its therapeutic potential for neurological disorders.