Neuroimmunomodulation Research Group, Department of Pathology, School of Veterinary Medicine, University of São Paulo (USP), São Paulo, Brazil.
Neuroimmune Interactions Laboratory, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:468-476. doi: 10.1016/j.pnpbp.2017.05.003. Epub 2017 May 9.
The wake-promoting drug Modafinil has been used for many years for treatment of Narcolepsy and Excessive Daytime Sleepiness, due to a dopamine-related psychostimulant action. Recent studies have indicated that Modafinil prevents neuroinflammation in animal models. Thus, the aim of the present study was to evaluate the effect of Modafinil pretreatment in the Lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors. Adult male C57BL/6J mice were pretreated with Vehicle or Modafinil (90mg/Kg) and, 30min later, received a single saline or LPS (2mg/Kg) administration, and were submitted to the open field and elevated plus maze test 2h later. After 24h, mice were subjected to tail suspension test, followed by either flow cytometry with whole brain for CD11bCD45 cells or qPCR in brain areas for cytokine gene expression. Modafinil treatment prevented the LPS-induced motor impairment, anxiety-like and depressive-like behaviors, as well as the increase in brain CD11bCD45 cells induced by LPS. Our results indicate that Modafinil pretreatment also decreased the IL-1β gene upregulation caused by LPS in brain areas, which is possibly correlated with the preventive behavioral effects. The pharmacological blockage of the dopaminergic D1R by the drug SCH-23390 counteracted the effect of Modafinil on locomotion and anxiety-like behavior, but not on depressive-like behavior and brain immune cells. The dopaminergic D1 receptor signaling is essential to the Modafinil effects on LPS-induced alterations in locomotion and anxiety, but not on depression and brain macrophages. This evidence suggests that Modafinil treatment might be useful to prevent inflammation-related behavioral alterations, possibly due to a neuroimmune mechanism.
促觉醒药物莫达非尼已被用于治疗嗜睡症和日间过度嗜睡症多年，这是由于其具有多巴胺相关的精神刺激作用。最近的研究表明，莫达非尼可预防动物模型中的神经炎症。因此，本研究旨在评估莫达非尼预处理对脂多糖（LPS）诱导的疾病和抑郁样行为的影响。成年雄性 C57BL/6J 小鼠用载体或莫达非尼（90mg/kg）预处理，30min 后，接受单次生理盐水或 LPS（2mg/kg）给药，并在 2h 后进行旷场和高架十字迷宫测试。24h 后，小鼠进行悬尾试验，随后对整个大脑的 CD11bCD45 细胞进行流式细胞术或大脑区域的 qPCR 检测细胞因子基因表达。莫达非尼治疗可预防 LPS 引起的运动障碍、焦虑样和抑郁样行为，以及 LPS 引起的大脑 CD11bCD45 细胞增加。我们的结果表明，莫达非尼预处理还降低了 LPS 在大脑区域引起的 IL-1β基因上调，这可能与预防行为作用有关。药物 SCH-23390 对多巴胺 D1R 的药理学阻断作用抵消了莫达非尼对运动和焦虑样行为的作用，但对抑郁样行为和大脑免疫细胞没有作用。多巴胺 D1 受体信号对于莫达非尼对 LPS 诱导的运动和焦虑改变的作用是必需的，但对于抑郁和大脑巨噬细胞则不是。这一证据表明，莫达非尼治疗可能有助于预防与炎症相关的行为改变，这可能是由于神经免疫机制。
