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首页> 外文期刊>Cellular Signalling >Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: Role of fluoxetine
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Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: Role of fluoxetine

机译：炎症诱导的行为变化是通过在小鼠海马的NRF2依赖性细胞凋亡和自噬的改变驱动的：氟西汀的作用

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Inflammation has been associated with the progression of many neurological diseases. Peripheral inflammation has also been vaguely linked to depression-like symptoms in animal models, but the underlying pathways that orchestrate inflammation-induced behavioral or molecular changes in the brain are still elusive. We have recently shown that intraperitoneal injections of lipopolysaccharide (LPS) to Swiss albino mice triggers systemic inflammation, leading to an activated immune response along with changes in monoamine levels in the brain. Herein we pinpoint the fundamental pathways linking peripheral inflammation and depression-like behavior in a mouse model, thereby identifying suitable targets of intervention to combat the situation. We show that LPS-induced peripheral inflammation provoked a depression-like behavior in mice and a distinct pro-inflammatory bias in the hippocampus, as evident from increased microglial activation and elevated levels of pro-inflammatory cytokines IL-6 and TNF-alpha, and activation of NF kappa B-p65 pathway. Significant alterations in Nrf2-dependent cellular redox status, coupled with altered autophagy and increased apoptosis were noticed in the hippocampus of LPS-exposed mice. We and others have previously shown that, fluoxetine (an anti-depressant) has effective antiinflammatory and antioxidant properties by virtue of its abilities to regulate NF kappa B and Nrf2 signaling. We observed that treatment with fluoxetine or the Nrf2 activator tBHQ (tert-butyl hydroquinone), could reverse depression-like-symptoms and mitigate alterations in autophagy and cell death pathways in the hippocampus by activating Nrf2-dependent gene expressions. Taken together, the data suggests that systemic inflammation potentiates Nrf2-dependent changes in cell death and autophagy pathway in the hippocampus, eventually leading to major pathologic sequelae associated with depression. Therefore, targeting Nrf2 could be a novel approach in combatting depression and ameliorating its associated pathogenesis.
机译：炎症与许多神经疾病的进展有关。外周血炎症也含糊地与动物模型中的抑郁状症状相关联，但协调炎症诱导的脑内的潜在途径仍然难以捉摸。我们最近表明，腹腔内注射脂多糖（LPS）对瑞士白化小鼠触发系统性炎症，导致激活的免疫应答以及大脑中单胺水平的变化。在此，我们确定在小鼠模型中将外周血炎症和抑郁样行为连接的基本途径，从而识别适当的干预目标来打击这种情况。我们表明，LPS诱导的外周炎症引起小鼠的抑郁状行为和海马中的明显的促炎偏倚，从增加的小胶质激活和促炎细胞因子IL-6和TNF-α的升高和TNF-α显而易见NF Kappa B-P65途径的激活。在LPS暴露小鼠的海马中发现了与改变的自噬和增加的凋亡相结合的NRF2依赖性细胞氧化还原状态的显着改变。我们和其他人之前已经表明，氟西汀（抗抑郁药）通过其能力来调节NF Kappa B和NRF2信号传导具有有效的抗炎和抗氧化特性。我们观察到，用氟苯胺汀或NRF2活化剂TBHQ（叔丁基醌）的处理可以通过激活NRF2依赖性基因表达来逆转抑制样症状并减轻海马自噬和细胞死亡途径的改变。在一起，数据表明，全身性炎症增强了海马中细胞死亡和自噬途径的NRF2依赖性变化，最终导致与抑郁症相关的主要病理后遗症。因此，靶向NRF2可以是对抗抑郁和改善其相关发病机制的新方法。

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