TLR4/NF-κB 通路对脑小血管病大鼠记忆功能及炎症因子的影响。

Influences of the TLR4/NF-κB pathway on memory function and inflammatory factors in rats with cerebral small vessel disease.

机构信息

Department of Neurology, Beijing Jishuitan Hospital, Beijing, China.

出版信息

Eur Rev Med Pharmacol Sci. 2019 Jul;23(14):6264-6271. doi: 10.26355/eurrev_201907_18447.

DOI:10.26355/eurrev_201907_18447

PMID:31364129

Abstract

OBJECTIVE

To explore the influences of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway on the memory function and inflammatory factors in rats with cerebral small vessel disease (CSVD).

MATERIALS AND METHODS

CSVD model in rats was established. Expressions of TLR4/NF-κB-related proteins and inflammatory factors were detected. CSVD rats were treated with the TLR4/NF-κB pathway agonist and inhibitor to evaluate the regulatory effect of TLR4/NF-κB pathway on the expressions of TLR4, NF-κB p50 and NF-κB p65. Moreover, their influences on the cerebral edema, memory function and expressions of inflammatory factors [interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)] in CSVD rats were also analyzed.

RESULTS

In model group, the mRNA and protein expressions of TLR4 and NF-κB-related proteins in rat hippocampus were significantly higher than those in sham group (p<0.01), and the expressions of IL-1β and TNF-αsignificantly increased (p<0.05). The agonist lipopolysaccharide (LPS) significantly increased the proportion of TLR4-positive cells (p<0.01) and protein expression of TLR4 (p<0.01). The inhibitor CLI-095 obviously reduced the proportion of TLR4-positive cells and TLR4 expression (p<0.05). Pyrrolidine dithiocarbamate (PDTC) remarkably reduced the expressions of NF-κB p50 and NF-κB p65 in model group (p<0.05). LPS promoted cerebral edema, leading to memory dysfunction and enhanced inflammatory response in rats of model group. The inhibitor CLI-095+PDTC significantly reduced cerebral edema, lowered memory impairment and relieved inflammatory response in CSVD rats (p<0.05).

CONCLUSIONS

The inhibitor of the TLR4/NF-κB signaling pathway can restore memory function and reduce inflammatory response in CSVD rats.

摘要

目的

探讨 Toll 样受体 4/核因子-κB（TLR4/NF-κB）通路对脑小血管病（CSVD）大鼠记忆功能和炎症因子的影响。

材料和方法

建立 CSVD 大鼠模型。检测 TLR4/NF-κB 相关蛋白和炎症因子的表达。用 TLR4/NF-κB 通路激动剂和抑制剂处理 CSVD 大鼠，评估 TLR4/NF-κB 通路对 TLR4、NF-κB p50 和 NF-κB p65 表达的调节作用。此外，还分析了它们对 CSVD 大鼠脑水肿、记忆功能和炎症因子[白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）]表达的影响。

结果

在模型组，大鼠海马 TLR4 和 NF-κB 相关蛋白的 mRNA 和蛋白表达均明显高于假手术组（p<0.01），IL-1β 和 TNF-α 的表达明显增加（p<0.05）。TLR4 激动剂脂多糖（LPS）显著增加 TLR4 阳性细胞的比例（p<0.01）和 TLR4 蛋白的表达（p<0.01）。抑制剂 CLI-095 明显降低 TLR4 阳性细胞和 TLR4 表达的比例（p<0.05）。吡咯烷二硫代氨基甲酸盐（PDTC）显著降低模型组 NF-κB p50 和 NF-κB p65 的表达（p<0.05）。LPS 促进脑水肿，导致模型组大鼠记忆功能障碍和炎症反应增强。抑制剂 CLI-095+PDTC 可显著减轻 CSVD 大鼠脑水肿，降低记忆障碍，减轻炎症反应（p<0.05）。