Zhuang Fuzhi, Zhou Xue, Gao Xin, Lou Dan, Bi Xuesheng, Qin Shoujun, Sun Chuxiao, Ye Peng, Wang Yun, Ma Tengfei, Li Mei, Gu Shuling
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Xuzhou 221004, China.
Peptides. 2016 Feb;76:115-29. doi: 10.1016/j.peptides.2016.01.002. Epub 2016 Jan 15.
Little is known about the physiological or pharmacological properties of alarin, a new neuropeptide belonging to the galanin family. We previously showed that alarin has an antidepressant-like effect and is associated with a decrease in the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis that is observed in patients with depression using unpredictable chronic mild stress (UCMS) mouse model of depression. However, the mechanisms underlying these effects have not been uncovered. Inflammatory cytokines are reportedly associated with depression. Animal studies and cytokine immune therapy in humans suggest that pro-inflammatory cytokines induce depressive symptomatology and potently activate the HPA axis, whereas anti-inflammatory cytokines may decrease activation. Thus, we first determined the levels of inflammatory cytokines in the blood and brain to evaluate whether the antidepressant-like effect of alarin in UCMS-treated mice is related to its regulation of these inflammatory cytokines. Pro-inflammatory cytokines disrupt the function and/or expression of glucocorticoid receptors (GRs), which mediate the negative feedback of glucocorticoids on the HPA axis to keep it from being overactivated. We next explored the expression level of GRs in the brains of mice subjected to UCMS and to the administration of alarin. We found that intracerebroventricular administration of alarin significantly ameliorated depression-like behaviors in the UCMS-treated mice. Alarin restored the UCMS-induced an increase in the levels of the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor α and a decrease in the anti-inflammatory cytokine IL-10 level in the blood, prefrontal cortex, hippocampus and hypothalamus. Alarin also reversed the UCMS-induced down-regulation of GR expression in these brain regions. Thus, the antidepressant-like effects of alarin may be mediated by restoring altered pro-inflammatory and anti-inflammatory cytokine levels and GR expression to decrease HPA axis hyperactivity. Our findings provide additional knowledge to interpret the pathophysiology of depression.
关于阿拉瑞林（一种属于甘丙肽家族的新型神经肽）的生理或药理特性，人们所知甚少。我们之前表明，阿拉瑞林具有抗抑郁样作用，并且与使用不可预测慢性轻度应激（UCMS）抑郁小鼠模型所观察到的抑郁症患者下丘脑 - 垂体 - 肾上腺（HPA）轴的亢进减少有关。然而，这些作用背后的机制尚未被揭示。据报道，炎性细胞因子与抑郁症有关。动物研究和人类细胞因子免疫疗法表明，促炎细胞因子可诱导抑郁症状并有力地激活HPA轴，而抗炎细胞因子可能会降低其激活。因此，我们首先测定了血液和大脑中炎性细胞因子的水平，以评估阿拉瑞林在UCMS处理小鼠中的抗抑郁样作用是否与其对这些炎性细胞因子的调节有关。促炎细胞因子会破坏糖皮质激素受体（GRs）的功能和/或表达，而GRs介导糖皮质激素对HPA轴的负反馈，以防止其过度激活。接下来，我们探究了接受UCMS处理并给予阿拉瑞林的小鼠大脑中GRs的表达水平。我们发现，脑室内注射阿拉瑞林可显著改善UCMS处理小鼠的抑郁样行为。阿拉瑞林恢复了UCMS诱导的血液、前额叶皮质、海马体和下丘脑促炎细胞因子白细胞介素（IL）-6和肿瘤坏死因子α水平的升高以及抗炎细胞因子IL-10水平降低。阿拉瑞林还逆转了UCMS诱导的这些脑区GR表达的下调。因此，阿拉瑞林的抗抑郁样作用可能是通过恢复改变的促炎和抗炎细胞因子水平以及GR表达来降低HPA轴亢进介导的。我们的研究结果为解释抑郁症的病理生理学提供了更多知识。
