Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Nørrebrogade 44, Building 2B, 8000 Aarhus, Denmark; Core Center for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Nørrebrogade 44, Building 2B, 8000 Aarhus, Denmark.
Eur Neuropsychopharmacol. 2021 Jan;42:45-56. doi: 10.1016/j.euroneuro.2020.11.008. Epub 2020 Nov 14.
We have previously reported that vortioxetine, unlike the selective serotonin reuptake inhibitor fluoxetine, produces a rapid increase of dendritic spine number and Brain Derived Neurotrophic Factor (BDNF)-associated formation of synapses with mitochondrial support in the rat hippocampal CA1 and dentate gyrus. As a continuation of this line of research, and given the putative role of brain glial cells in mediating antidepressant responses the present study investigated early effects of vortioxetine on hippocampal microvasculature and Vascular Endothelial Growth Factor (VEGF) and astrocytes and microglia cells. Rats were treated for 1 week with vortioxetine (1.6 g/kg food chow) or fluoxetine (160 mg/L drinking water) at pharmacologically relevant doses. Stereological principles were used to estimate the number of ALDH1L1 positive astrocytes and Iba1 positive microglia cells, and the length of microvessels in subregions of hippocampus. VEGF protein levels were visualized with immunohistochemistry. Our results showed that vortioxetine significantly increased the number of ramified (resting) microglia and astrocytes accompanied by VEGF level elevation, whereas fluoxetine had no effect after 7 days treatment on these measures. Our findings suggest that astrocytes and microglia may have a role in mediating the pharmacological effects of vortioxetine in rats and that these effects are mediated through mechanisms that go beyond inhibition of the serotonin transporter and may target specific 5-HT receptors. It remains to be investigated whether these findings are relevant for the therapeutic effects of vortioxetine.
我们之前曾报道过，与选择性 5-羟色胺再摄取抑制剂氟西汀不同，文拉法辛能迅速增加大鼠海马 CA1 和齿状回的树突棘数量和与脑源性神经营养因子（BDNF）相关的突触形成，并提供线粒体支持。作为这一研究方向的延续，鉴于脑胶质细胞在介导抗抑郁反应中的潜在作用，本研究探讨了文拉法辛对海马微血管和血管内皮生长因子（VEGF）以及星形胶质细胞和小胶质细胞的早期影响。大鼠用文拉法辛（1.6g/kg 食物）或氟西汀（160mg/L 饮用水）以药理学相关剂量处理 1 周。应用体视学原理来估计 ALDH1L1 阳性星形胶质细胞和 Iba1 阳性小胶质细胞的数量，以及海马亚区中小血管的长度。用免疫组织化学法显示 VEGF 蛋白水平。结果表明，文拉法辛显著增加了分支（静止）小胶质细胞和星形胶质细胞的数量，并伴有 VEGF 水平升高，而氟西汀在 7 天治疗后对这些指标没有影响。我们的发现表明，星形胶质细胞和小胶质细胞可能在介导文拉法辛在大鼠中的药理作用方面发挥作用，这些作用是通过超越抑制 5-羟色胺转运体的机制介导的，并且可能针对特定的 5-HT 受体。尚需研究这些发现是否与文拉法辛的治疗效果有关。
