Obuchowicz Ewa, Bielecka-Wajdman Anna, Zieliński Michał, Machnik Grzegorz, Gołyszny Miłosz, Ludyga Tomasz
Department of Pharmacology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Katowice, Poland.
Department of Internal Medicine and Clinical Pharmacology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Katowice, Poland.
Front Pharmacol. 2020 Jan 31;10:1687. doi: 10.3389/fphar.2019.01687. eCollection 2019.
Here, we examine the effects of prenatal administration of two antidepressants-imipramine (IMI) and venlafaxine (VEN)-on morphology and activity of a primary glial culture. Microglia are targeted by antidepressants used for antenatal depression and are important regulators of central nervous system development. In this study, female Wistar rats were assigned to one of four groups: a control group that received water (1), and groups that received additionally once daily either water (2), IMI (10 mg/kg) (3), or VEN (20 mg/kg) (4) by oral gavage from gestation day 7 to 22. Oral gavage administration induced prenatal stress. Cell cultures were obtained from the brains of 1-day-old pups. Prenatal stress caused a disturbance of sensorimotor function in pups. Prenatal stress also produced alterations in the glial cultures, specifically, an increased percentage of microglia in the mixed glial cultures and an increased percentage of dead cells. Moreover, increased levels of IL1-β, TNF-α, NO, and an increased expression of CX3CR1 mRNA were found in microglia. However, the ratio of Bax/Bcl2 mRNA was reduced. Prenatal stress increased the vulnerability of microglia to lipopolysaccharide (LPS). The mixed glial culture derived from pups exposed to IMI showed greater morphological changes and the highest percentage of microglia. Microglia were characterized by the largest increase in the production of pro-inflammatory cytokines and NO, and the greatest reduction in the expression of CX3CR1 mRNA. Exposure to IMI reduced the effects of LPS on IL-1β production and Bax/Bcl2 mRNA, and exacerbated the effects of LPS on CX3CR1 mRNA expression. Prenatal administration of VEN induced protective effects on microglia, as measured by all studied parameters. Taken together, our data suggest that, by disturbing microglia function, exposure to even mild forms of chronic prenatal stress may predispose individuals to psychiatric or neurodevelopmental disorders. These data also indicate that chronic mild stress sensitizes microglia to immune challenges, which may lead to enhanced neuronal damage in the embryonic brain. The observed detrimental effects of IMI on microglial activity under conditions of prenatal stress may help to explain the teratogenic effects of IMI reported in the literature.
在此，我们研究了产前给予两种抗抑郁药——丙咪嗪（IMI）和文拉法辛（VEN）——对原代神经胶质细胞培养物的形态和活性的影响。小胶质细胞是用于治疗产前抑郁症的抗抑郁药的作用靶点，并且是中枢神经系统发育的重要调节因子。在本研究中，将雌性Wistar大鼠分为四组之一：接受水的对照组（1），以及从妊娠第7天至22天通过口服灌胃每天额外接受一次水（2）、IMI（10 mg/kg）（3）或VEN（20 mg/kg）（4）的组。口服灌胃给药会引起产前应激。从1日龄幼崽的大脑中获取细胞培养物。产前应激导致幼崽感觉运动功能紊乱。产前应激还会使神经胶质细胞培养物发生改变，具体而言，混合神经胶质细胞培养物中小胶质细胞的百分比增加，死亡细胞的百分比增加。此外，在小胶质细胞中发现白细胞介素-1β（IL1-β）、肿瘤坏死因子-α（TNF-α）、一氧化氮（NO）水平升高，以及CX3CR1 mRNA表达增加。然而，Bax/Bcl2 mRNA的比率降低。产前应激增加了小胶质细胞对脂多糖（LPS）的易感性。来自暴露于IMI的幼崽的混合神经胶质细胞培养物显示出更大的形态变化和最高百分比的小胶质细胞。小胶质细胞的特征在于促炎细胞因子和NO的产生增加最多，以及CX3CR1 mRNA的表达减少最多。暴露于IMI可降低LPS对IL-1β产生和Bax/Bcl2 mRNA的影响，并加剧LPS对CX3CR1 mRNA表达的影响。通过所有研究参数测量，产前给予VEN对小胶质细胞具有保护作用。综上所述，我们的数据表明，即使是轻度形式的慢性产前应激暴露，通过干扰小胶质细胞功能，可能使个体易患精神或神经发育障碍。这些数据还表明，慢性轻度应激使小胶质细胞对免疫挑战敏感，这可能导致胚胎大脑中神经元损伤加剧。在产前应激条件下观察到的IMI对小胶质细胞活性的有害影响可能有助于解释文献中报道的IMI的致畸作用。
