Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan; Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan.
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan.
Chem Biol Interact. 2022 Jan 5;351:109767. doi: 10.1016/j.cbi.2021.109767. Epub 2021 Dec 1.
The present study investigated the role of neuroinflammation and brain oxidative stress induced by neonatal treatment with lipopolysaccharides (LPS) on the development of autism spectrum disorder (ASD)-like behaviors and disruptive hippocampal neurogenesis in rats by exploring the chemopreventive effects of alpha-glycosyl isoquercitrin (AGIQ) as an antioxidant. AGIQ was dietary administered to dams at 0.25% or 0.5% (w/w) from gestational day 18 until postnatal day (PND) 21 on weaning and then to pups until the adult stage on PND 77. The pups were intraperitoneally injected with LPS (1 mg/kg body weight) on PND 3. At PND 6, LPS alone increased Iba1 and CD68 cell numbers without changing the CD163 cell number and strongly upregulated pro-inflammatory cytokine gene expression (Il1a, Il1b, Il6, Nfkb1, and Tnf) in the hippocampus, and increased brain malondialdehyde levels. At PND 10, pups decreased ultrasonic vocalization (USV), suggesting the induction of pro-inflammatory responses and oxidative stress to trigger communicative deficits. By contrast, LPS alone upregulated Nfe2l2 expression at PND 6, increased Iba1, CD68, and CD163 cell numbers, and upregulated Tgfb1 at PND 21, suggesting anti-inflammatory responses until the weaning period. However, LPS alone disrupted hippocampal neurogenesis at weaning and suppressed social interaction parameters and rate of freezing time at fear acquisition and extinction during the adolescent stage. On PND 77, neuroinflammatory responses had mostly disappeared; however, disruptive neurogenesis and fear memory deficits were sustained. AGIQ ameliorated most changes on acute pro-inflammatory responses and oxidative stress at PND 6, and the effects on USVs at PND 10 and neurogenesis and behavioral parameters throughout the adult stage. These results suggested that neonatal LPS treatment induced acute but transient neuroinflammation, triggering the progressive disruption of hippocampal neurogenesis leading to abnormal behaviors in later life. AGIQ treatment was effective for ameliorating LPS-induced progressive changes by critically suppressing initial pro-inflammatory responses and oxidative stress.
本研究通过探索抗氧化剂α-糖苷基异槲皮苷 (AGIQ) 的化学预防作用，研究了新生期脂多糖 (LPS) 处理诱导的神经炎症和大脑氧化应激对大鼠自闭症谱系障碍 (ASD) 样行为和海马神经发生的破坏作用。AGIQ 从妊娠第 18 天到断奶后的第 21 天以 0.25%（w/w）或 0.5%（w/w）的剂量添加到饮食中，然后给幼崽喂食至第 77 天成年。幼崽在出生后第 3 天腹膜内注射 LPS（1mg/kg 体重）。在出生后第 6 天，LPS 单独增加了 Iba1 和 CD68 细胞数量，而不改变 CD163 细胞数量，并强烈上调了海马中的促炎细胞因子基因表达（Il1a、Il1b、Il6、Nfkb1 和 Tnf），并增加了脑丙二醛水平。在出生后第 10 天，幼崽减少了超声波发声（USV），表明促炎反应和氧化应激的诱导引发了交流缺陷。相比之下，LPS 单独在出生后第 6 天上调了 Nfe2l2 表达，增加了 Iba1、CD68 和 CD163 细胞数量，并在出生后第 21 天上调了 Tgfb1，表明在断奶期之前存在抗炎反应。然而，LPS 单独在断奶时破坏了海马神经发生，并在青少年期抑制了恐惧获得和消退期间的社交互动参数和冻结时间率。在出生后第 77 天，神经炎症反应大多消失；然而，神经发生和记忆缺陷仍持续存在。AGIQ 改善了出生后第 6 天急性促炎反应和氧化应激的大多数变化，以及出生后第 10 天 USV 的变化，并在整个成年期改善了神经发生和行为参数。这些结果表明，新生期 LPS 处理诱导了急性但短暂的神经炎症，触发了海马神经发生的进行性破坏，导致生命后期出现异常行为。AGIQ 治疗通过严格抑制初始促炎反应和氧化应激，对 LPS 诱导的进行性变化具有治疗作用。
