Chotosan improves Aβ_1-42-induced cognitive impairment and neuroinflammatory and apoptotic responses through the inhibition of TLR-4/NF-κB signaling in mice

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• 作者：Lei Chen^a ; Lejian Hu^a ; Jiaojiao Zhao^a ; Hao Hong^c ; Feng Feng^a ; ^{fengfeng@cpu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Wei Qu^a ; Wenyuan Liu^b ; ^{liuwenyuan8506@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Alzheimer's disease ; Chotosan ; Toll-like receptor 4 ; Neuroinflammation ; Apoptosis
• 刊名：Journal of Ethnopharmacology
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：191
• 期：Complete
• 页码：398-407
• 全文大小：1630 K

文摘

Recently, the focus on neuroinflammation is intensified as its complex pathophysiological role has emerged in multiple central nervous system(CNS) disorders. Chotosan (CTS), known as a traditional herbal formula, is often utilized to treat relevant nervous system diseases in China. It was demonstrated effectively to alleviate cognitive deficit associated with aging, diabetes, hypoperfusion and cerebral ischemia. However, the effects of CTS on Aβ_1–42-induced cognitive dysfunction remain unclear. Here, we further investigated the effects of chotosan on memory performance, neuroinflammation and apoptotic responses.

Materials and methods

The learning and memory ability is evaluated by Morris water maze (MWM) task and Y-maze test following intrahippocampal infusion of aggregated Aβ_1–42. The expression level of toll-like receptor 4 (TLR-4), NF-κB p65, Bcl-2 and Bax was examined by Western blot. TLR-4 level is also assessed by immunohistochemistry (IHC). Enzyme-linked immunosorbent assay (ELISA) was conducted to determine the generation of inflammatory mediators. The caspase-3 activity is analyzed by commercial kits.

Results

The repeated treatment with CTS (750 mg/kg or 375 mg/kg per day) for 3 weeks significantly restored Aβ_1–42-induced memory impairment in mice. Meanwhile, this treatment also remarkably reduced TLR-4 and NF-κB p65 expression accompanying with the diminished release of proinflammatory cytokines including TNF-α and IL-1β in hippocampus. The neuronal apoptosis is also inhibited as evidenced by increase in Bcl-2/Bax ratio and decrease in pro-apoptotic protein caspase-3 activity compared to that of the model mice.

Conclusions

Our results show for the first time that chotosan can ameliorate Aβ_1–2-induced memory dysfunction via inhibiting neuroinflammation and apoptosis at least partially mediated by TLR-4/NF-κB signaling pathway.