Tang Qian, Takashima Kazumi, Zeng Wen, Okano Hiromu, Zou Xinyu, Takahashi Yasunori, Ojiro Ryota, Ozawa Shunsuke, Koyanagi Mihoko, Maronpot Robert R, Yoshida Toshinori, Shibutani Makoto
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology.
Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology.
J Toxicol Sci. 2023;48(3):121-137. doi: 10.2131/jts.48.121.
This study investigated the role of neuroinflammation in a lipopolysaccharides (LPS)-induced cognitive dysfunction model in rats using an antioxidant, α-glycosyl isoquercitrin (AGIQ). Six-week-old rats were dietary treated with 0.5% (w/w) AGIQ for 38 days, and LPS at 1 mg/kg body weight was administered intraperitoneally once daily on Days 8 and 10. On Day 11, LPS alone increased or tended to increase interleukin-1β and tumor necrosis factor-α in the hippocampus and cerebral cortex. Immunohistochemically, LPS alone increased the number of Iba1 and CD68 microglia, and GFAP astrocytes in the hilus of the hippocampal dentate gyrus (DG). AGIQ treatment decreased or tended to decrease brain proinflammatory cytokine levels and the number of CD68 microglia in the DG hilus. In the contextual fear conditioning test during Day 34 and Day 38, LPS alone impaired fear memory acquisition, and AGIQ tended to recover this impairment. On Day 38, LPS alone decreased the number of DCX cells in the neurogenic niche, and AGIQ increased the numbers of PCNA cells in the subgranular zone and CALB2 hilar interneurons. Additionally, LPS alone decreased or tended to decrease the number of synaptic plasticity-related FOS and COX2 granule cells and AGIQ recovered them. The results suggest that LPS administration induced acute neuroinflammation and subsequent impairment of fear memory acquisition caused by suppressed synaptic plasticity of newborn granule cells following disruptive neurogenesis. In contrast, AGIQ exhibited anti-inflammatory effects and ameliorated LPS-induced adverse effects. These results suggest that neuroinflammation is a key factor in the development of LPS-induced impairment of fear memory acquisition.
本研究使用抗氧化剂α-糖基异槲皮苷（AGIQ），在脂多糖（LPS）诱导的大鼠认知功能障碍模型中研究了神经炎症的作用。六周龄大鼠用0.5%（w/w）AGIQ进行饮食处理38天，在第8天和第10天每天腹腔注射1mg/kg体重的LPS一次。在第11天，单独使用LPS会增加或倾向于增加海马体和大脑皮层中的白细胞介素-1β和肿瘤坏死因子-α。免疫组织化学结果显示，单独使用LPS会增加海马齿状回（DG）门区中Iba1和CD68小胶质细胞以及GFAP星形胶质细胞的数量。AGIQ处理可降低或倾向于降低大脑促炎细胞因子水平以及DG门区中CD68小胶质细胞的数量。在第34天和第38天的情境恐惧条件反射测试中，单独使用LPS会损害恐惧记忆的获取，而AGIQ倾向于恢复这种损害。在第38天,单独使用LPS会减少神经源性小生境中双皮质素（DCX）细胞的数量，而AGIQ会增加颗粒下区增殖细胞核抗原（PCNA）细胞和钙结合蛋白2（CALB2）门区中间神经元的数量。此外，单独使用LPS会减少或倾向于减少与突触可塑性相关的FOS和环氧化酶2（COX2）颗粒细胞的数量，而AGIQ可使其恢复。结果表明，LPS给药会诱导急性神经炎症，并随后导致恐惧记忆获取受损，这是由于神经发生紊乱后新生颗粒细胞的突触可塑性受到抑制所致。相比之下，AGIQ具有抗炎作用，并改善了LPS诱导的不良反应。这些结果表明，神经炎症是LPS诱导恐惧记忆获取受损的关键因素。
