Wang Junhui, Qiao Jinping, Zhang Yanbo, Wang Hongxing, Zhu Shenghua, Zhang Handi, Hartle Kelly, Guo Huining, Guo Wei, He Jue, Kong Jiming, Huang Qingjun, Li Xin-Min
Mental Health Center, Shantou University, Shantou, Guangdong, China.
Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
J Neurochem. 2014 Oct;131(2):229-38. doi: 10.1111/jnc.12792. Epub 2014 Jul 8.
Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.
血清素/去甲肾上腺素再摄取抑制剂类抗抑郁药通过增加突触间隙中的血清素和去甲肾上腺素来发挥作用。研究表明，其改善情绪的效果需要2至3周才能显现，这表明可能还有其他机制在其治疗效果中起作用。在此，我们使用不可预测的慢性轻度应激（UCMS）小鼠模型研究了白质在抑郁症治疗和发病机制中的作用。在UCMS小鼠经历为期7周的应激程序前1周，以10毫克/千克/天的剂量给它们口服地文拉法辛（DVS），持续给药超过8周后处死小鼠。在UCMS小鼠中，未发现神经元和星形胶质细胞的蛋白质标志物有显著变化。然而，UCMS小鼠中与髓磷脂和少突胶质细胞相关的蛋白质显著减少。DVS可防止应激对白质造成的损伤以及磷酸化的5'-AMP激活蛋白激酶和3-羟基-3-甲基戊二酰辅酶A还原酶蛋白表达的降低。在高架十字迷宫试验中，DVS增加了小鼠进入开放臂的次数；在蔗糖偏好试验中，增加了蔗糖消耗量；在悬尾试验和强迫游泳试验中，减少了小鼠的不动时间。这些发现表明，应激会在UCMS小鼠中诱发类似抑郁的行为和白质缺陷。DVS可能通过影响胆固醇合成来改善少突胶质细胞功能障碍，从而减轻这些小鼠的类似抑郁的表型。我们用不可预测的慢性轻度应激（UCMS）小鼠模型研究了少突胶质细胞和髓磷脂在抑郁症病理变化中的可能作用。在应激期间，小鼠大脑中与少突胶质细胞相关的蛋白质发生了特异性变化。给予地文拉法辛可预防类似抑郁的行为和少突胶质细胞缺陷。少突胶质细胞和髓磷脂可能是地文拉法辛治疗抑郁症的重要靶点。
