Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur-Italy, Sapienza University of Rome, Italy.
Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.
Brain Behav Immun. 2019 Oct;81:484-494. doi: 10.1016/j.bbi.2019.07.003. Epub 2019 Jul 4.
An increasing number of studies show that both inflammation and neural plasticity act as key players in the vulnerability and recovery from psychiatric disorders and neurodegenerative diseases. However, the interplay between these two players has been limitedly explored. In fact, while a few studies reported an immune activation, others conveyed an immune suppression, associated with an impairment in neural plasticity. Therefore, we hypothesized that deviations in inflammatory levels in both directions may impair neural plasticity. We tested this hypothesis experimentally, by acute treatment of C57BL/6 adult male mice with different doses of two inflammatory modulators: lipopolysaccharide (LPS), an endotoxin, and ibuprofen (IBU), a nonselective cyclooxygenase inhibitor, which are respectively a pro- and an anti-inflammatory agent. The results showed that LPS and IBU have different effects on behavior and inflammatory response. LPS treatment induced a reduction of body temperature, a decrease of body weight and a reduced food and liquid intake. In addition, it led to increased levels of inflammatory markers expression, both in the total hippocampus and in isolated microglia cells, including Interleukin (IL)-1β, and enhanced the concentration of prostaglandin E (PGE). On the other hand, IBU increased the level of anti-inflammatory markers, decreased tryptophan 2,3-dioxygenase (TDO2), the first step in the kynurenine pathway known to be activated during inflammatory conditions, and PGE levels. Though LPS and IBU administration differently affected mediators related with pro- or anti-inflammatory responses, they produced overlapping effects on neural plasticity. Indeed, higher doses of both LPS and IBU induced a statistically significant decrease in the amplitude of long-term potentiation (LTP), in Brain-Derived Neurotrophic Factor (BDNF) expression levels and in the phosphorylation of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluR1, compared to the control group. Such effect appears to be dose-dependent since only the higher, but not the lower, dose of both compounds led to a plasticity impairment. Overall, the present findings indicate that acute treatment with pro- and anti-inflammatory agents impair neural plasticity in a dose dependent manner.
越来越多的研究表明，炎症和神经可塑性都作为易患精神疾病和神经退行性疾病以及从中恢复的关键因素。然而，这两个因素之间的相互作用尚未得到充分探索。事实上，虽然一些研究报告了免疫激活，而另一些研究则报告了免疫抑制，这与神经可塑性的损害有关。因此，我们假设两个方向的炎症水平偏差都可能损害神经可塑性。我们通过急性治疗 C57BL/6 成年雄性小鼠不同剂量的两种炎症调节剂：脂多糖（LPS），一种内毒素，和布洛芬（IBU），一种非选择性环氧化酶抑制剂，分别是促炎和抗炎剂，来验证这个假设。结果表明，LPS 和 IBU 对行为和炎症反应有不同的影响。LPS 处理导致体温降低、体重减轻、食物和液体摄入减少。此外，它导致总海马体和分离的小胶质细胞中的炎症标志物表达水平增加，包括白细胞介素（IL）-1β，并增强了前列腺素 E（PGE）的浓度。另一方面，IBU 增加了抗炎标志物的水平，降低了色氨酸 2,3-双加氧酶（TDO2），即已知在炎症条件下被激活的犬尿氨酸途径的第一步，以及 PGE 水平。虽然 LPS 和 IBU 以不同的方式影响与促炎或抗炎反应相关的介质，但它们对神经可塑性产生了重叠的影响。事实上，两种 LPS 和 IBU 的较高剂量都导致长时程增强（LTP）的幅度、脑源性神经营养因子（BDNF）表达水平以及 AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）受体亚基 GluR1 的磷酸化统计学上显著降低，与对照组相比。这种效应似乎是剂量依赖性的，因为只有较高剂量的两种化合物而不是较低剂量的化合物导致了可塑性的损害。总的来说，目前的研究结果表明，急性使用促炎和抗炎剂以剂量依赖的方式损害神经可塑性。
