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-α, and activation of NFκB-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 anti-inflammatory and antioxidant properties by virtue of its abilities to regulate NFκB 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.

中文翻译：

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炎症诱导的行为变化是由小鼠海马中Nrf2依赖性凋亡和自噬的改变驱动的：氟西汀的作用。

炎症与许多神经系统疾病的进展有关。在动物模型中，周围炎症还与抑郁症样症状相关，但是协调炎症引起的大脑行为或分子变化的潜在途径仍然难以捉摸。我们最近发现，向瑞士的白化病小鼠腹腔注射脂多糖（LPS）会触发全身性炎症，导致激活的免疫反应以及脑中单胺水平的变化。在本文中，我们查明了在小鼠模型中将周围炎症和抑郁样行为联系起来的基本途径，从而确定了应对这种情况的合适干预目标。我们显示LPS诱导的周围炎症在小鼠中引起抑郁样行为，并在海马体中引起明显的促炎性偏见，这从增加的小胶质细胞激活和促炎性细胞因子IL-6和TNF-α的水平升高中可以明显看出，并且激活NFκB-p65途径。在暴露于LPS的小鼠海马中，发现了Nrf2依赖性细胞氧化还原状态的显着变化，以及自噬的改变和凋亡的增加。我们和其他人先前已经证明，氟西汀（一种抗抑郁药）凭借其调节NFκB和Nrf2信号传导的能力而具有有效的抗炎和抗氧化特性。我们观察到用氟西汀或Nrf2活化剂tBHQ（叔丁基对苯二酚）进行治疗，通过激活Nrf2依赖性基因表达，可以逆转抑郁症样症状并减轻海马体自噬和细胞死亡途径的改变。两者合计，数据表明全身性炎症会增强Nrf2依赖性海马细胞死亡和自噬途径的变化，最终导致与抑郁症相关的主要病理后遗症。因此，靶向Nrf2可能是抗击抑郁和改善其相关发病机制的新方法。