Abstract：
Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor-α (PPARα), with the clinically available agonist fenofibrate (FEN), attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine/growth factor levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 h after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/control (CTRL) group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-α), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1α levels were lower than in vehicle (veh)/CTRL group. Notably, MIP-1α, TNF-α, keratinocyte derived chemokine (GRO/KC), GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, suggesting the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate MIA-induced inflammation.
摘要：
孕妇在怀孕期间感染可能会增加后代患精神疾病的风险。我们最近证明了过氧化物酶体增殖物激活受体-α（PPARα）的激活，与临床上可用的激动剂非诺贝特（FEN），减轻大鼠后代母体免疫激活（MIA）引起的神经发育障碍。我们假设非诺贝特可能会减少MIA诱导的细胞因子失衡，使用基于病毒模拟物聚核糖胞嘧啶-聚核糖胞嘧啶酸[聚（I：C）]的MIA模型。通过使用Bio-Plex多重免疫测定系统，我们测量了非诺贝特治疗大鼠母体血清和胎儿脑中的细胞因子/趋化因子/生长因子水平，在聚(I:C)后6和24小时。我们发现MIA诱导了几种细胞因子/趋化因子/集落刺激因子（CSF）水平的时间依赖性变化。具体来说,聚（I：C）/对照（CTRL）组的母体血清显示（i）促炎趋化因子巨噬细胞炎性蛋白1-α（MIP-1α）水平升高，（ii）肿瘤坏死因子-α（TNF-α），单核细胞趋化蛋白-1（MCP-1），巨噬细胞(M-CSF)和粒细胞-巨噬细胞集落刺激因子(GM-CSF)。相反，在聚（I：C）/CTRL组的胎儿大脑中，白细胞介素12p70和MIP-1α水平低于溶媒(veh)/CTRL组。值得注意的是,MIP-1α,TNF-α,角质形成细胞来源的趋化因子（GRO/KC），GM-CSF,聚(I:C)/FEN中M-CSF水平低于聚(I:C)/CTRL大鼠,提示PPARα激动剂的保护作用。PPARα可能是减轻MIA诱导的炎症的治疗靶标。
