Anti-inflammatory Effect And Mechanism Of Hydroxy-safflor Yellow A （HSYA） In Aβ_1-42-induced Mice

Backgroud:Alzheimer’s disease (AD) is a chronic, progressive, neurodegenerative disorder characterized clinically with progressive cognitive impairment. The two major pathological hallmarks of AD are extraneuronal accumulation of beta-amyloid (Aβ) and intraneuronal deposition of hyperphosphorylated tau protein. Aβ-mediated inflammation plays a critical role in the initiation and progression of AD. Anti-inflammatory treatment may provide therapeutic benefits.Objectives:The aims of this study are:1) to investigate the effects of HSYA on Aβ1-42-induced inflammation in vitro and in vivo;2) to explore the mechanism underlying of HSYA on Aβ1-42-induced inflammation.Methods:Learning and memory impairment of Aβ1-42-induced mice were tested by Morris water maze. Immunofluorescent staining for glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule1(Ibal) in the hippocampi of mice was performed to determine the effect of HSYA on glial activation and inflammation. Real-time PCR was used to detect the mRNA levels of cytokines. To elucidate the mechanism of HSYA in suppression of inflammation, we detected the activity of NF-κB and JAK2/STAT3pathways in HSYA treated and untreated groups by western blot. To confirm the anti-inflammatory effects of HSYA confer neuroprotection, conditioned medium of Aβ1-42-treated BV-2cells with or without HSYA were collected to treat SH-SY5Y cells and primary neurons. The viability of SH-SY5Y cells and neurons was measured by MTT assay and AnnexinV/PI staining. Statistical analyses were performed using ANOVA and post hoc Fisher’s PLSD tests. P<0.05was considered to denote statistical significance. Results:HSYA administration significantly improved learning and memory impairments in Aβ1-42-induced mice. HSYA markedly inhibited the activation of microglia and astrocytes and down-regulated pro-inflammatory cytokines in AD mice. HSYA up-regulated the phosphorylation of JAK2/STAT3pathway and inhibited NF-κB activation. Pharmacological inhibition of STAT3by AG490reversed the inactivation of p65and anti-inflammatory effects of HSYA. HSYA prevented Aβ1-42-induced NF-κB activation in a STAT3-dependent manner.Conclusion:Inflammation played an important role in the pathogenesis of AD. HSYA protected Aβ1-42-induced AD model through inhibiting inflammatory response. The anti-inflammatory mechanisms might be related to JAK2-STAT3-NF-κB pathway.