Ishikawa Junko, Sutoh Chihiro, Ishikawa Akinori, Kagechika Hiroyuki, Hirano Hitoshi, Nakamura Shoji
Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan.
Eur J Neurosci. 2008 May;27(9):2363-72. doi: 10.1111/j.1460-9568.2008.06191.x.
Retinoids influence cellular processes such as differentiation, proliferation and apoptosis via retinoic acid receptor (RAR) and retinoid X receptor (RXR), and have therapeutic applications in several cancers and dermatologic diseases. Recent reports indicate that depression occasionally occurs in patients using the acne drug Accutane, the active component of which is 13-cis-retinoic acid (13-cis-RA). Although impairment of serotonin (5-HT)-expressing neurons, including morphologic changes, is thought to be associated with depressive symptoms, the effects of 13-cis-RA on 5-HT neurons have not been examined. The present study demonstrated that 13-cis-RA alters the morphology of 5-HT neurons in cultured rat midbrain slices. The 13-cis-RA-induced changes were partially blocked by RXR and RAR antagonists. Furthermore, cotreatment with RAR and RXR agonists altered the morphology of 5-HT neurons to a greater extent than the individual application of each agonist. The morphologic changes were completely blocked by RXR antagonist, whereas RAR antagonist partially blocked the effects. These results suggest that 13-cis-RA exerts its action on slice-cultured 5-HT neurons, at least in part, through specific retinoid receptors. Moreover, RXR has a greater influence on the morphology of 5-HT neurons than RAR. The receptor-mediated actions of 13-cis-RA presented here may provide a clue for further research on depression associated with the use of 13-cis-RA.
维甲酸通过维甲酸受体（RAR）和维甲酸X受体（RXR）影响细胞分化、增殖和凋亡等过程，并在多种癌症和皮肤病治疗中具有应用价值。最近的报告表明，使用痤疮药物异维甲酸（其活性成分是13-顺式维甲酸，13-cis-RA）的患者偶尔会出现抑郁症状。尽管人们认为血清素（5-HT）表达神经元的损伤（包括形态学变化）与抑郁症状有关，但尚未研究13-cis-RA对5-HT神经元的影响。本研究表明，13-cis-RA可改变培养的大鼠中脑切片中5-HT神经元的形态。13-cis-RA诱导的变化被RXR和RAR拮抗剂部分阻断。此外，RAR和RXR激动剂联合处理比单独应用每种激动剂更能改变5-HT神经元的形态。形态学变化被RXR拮抗剂完全阻断，而RAR拮抗剂部分阻断了这些作用。这些结果表明，13-cis-RA至少部分通过特定的维甲酸受体对切片培养的5-HT神经元发挥作用。此外，RXR对5-HT神经元形态的影响比RAR更大。本文展示的13-cis-RA的受体介导作用可能为进一步研究与使用13-cis-RA相关的抑郁症提供线索。
