Zhuang Fuzhi, Li Mei, Gao Xin, Wang Yun, Wang Dongdong, Ma Xing, Ma Tengfei, Gu Shuling
Department of Pharmacy, The First People's Hospital of Wujiang, Suzhou 215200, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical University, Xuzhou 221004, China.
Behav Brain Res. 2016 Oct 15;313:158-171. doi: 10.1016/j.bbr.2016.06.057. Epub 2016 Jun 30.
Alarin is a newly derived neuropeptide from a splice variant of the galanin-like peptide gene. We previously showed that alarin has an antidepressant-like effect by increasing the activity of the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways, mediated by the tropomyosin-related kinase B receptor in the unpredictable chronic mild stress (UCMS) mouse model. Administration of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, prevents the rapid antidepressant-like effect induced by ketamine in animal models, indicating a vital role of mTOR in depression pathophysiology. mTOR is a target of the ERK and AKT pathways that regulates the initiation of protein translation via its downstream components: ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). Therefore, we hypothesized that the antidepressant-like effects of alarin were achieved by activating ERK/AKT pathways, increasing the activity of mTOR and its downstream signaling components that contribute to protein synthesis required for synaptic plasticity. Our results suggest that intracerebroventricular administration of alarin significantly ameliorates depression-like behaviors in the UCMS mouse model. Furthermore, alarin restored UCMS-induced reductions of p70S6K and post-synaptic density 95 (PSD-95) mRNA levels, and of phospho-mTOR and phospho-4EBP1 in the prefrontal cortex, hippocampus, hypothalamus, and olfactory bulb. Additionally, alarin reversed the UCMS-induced downregulation of PSD-95 and synapsin I protein expression in these brain regions. Thus, the antidepressant-like effects of alarin may be mediated by restoring decreased activity of the mTOR signaling pathway and expression of synaptic proteins. Our findings help advance the understanding of depression pathophysiology.
阿拉瑞林是一种新发现的神经肽，源自甘丙肽样肽基因的剪接变体。我们之前的研究表明，在不可预测的慢性轻度应激（UCMS）小鼠模型中，阿拉瑞林通过增加细胞外信号调节激酶（ERK）和蛋白激酶B（AKT）信号通路的活性，发挥类似抗抑郁的作用，该作用由原肌球蛋白相关激酶B受体介导。雷帕霉素是一种哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，在动物模型中，给予雷帕霉素可阻止氯胺酮诱导的快速抗抑郁样效应，这表明mTOR在抑郁症病理生理学中起着至关重要的作用。mTOR是ERK和AKT信号通路的靶点，通过其下游成分核糖体蛋白S6激酶（p70S6K）和真核起始因子4E结合蛋白1（4E-BP1）调节蛋白质翻译的起始。因此，我们推测阿拉瑞林的抗抑郁样作用是通过激活ERK/AKT信号通路，增加mTOR及其下游信号成分的活性来实现的，这些成分有助于突触可塑性所需的蛋白质合成。我们的结果表明，脑室内注射阿拉瑞林可显著改善UCMS小鼠模型中的抑郁样行为。此外，阿拉瑞林恢复了UCMS诱导的前额叶皮质、海马体、下丘脑和嗅球中p70S6K和突触后密度95（PSD-95）mRNA水平以及磷酸化mTOR和磷酸化4EBP1的降低。此外，阿拉瑞林逆转了UCMS诱导的这些脑区中PSD-95和突触素I蛋白表达的下调。因此，阿拉瑞林的抗抑郁样作用可能是通过恢复mTOR信号通路活性降低和突触蛋白表达来介导的。我们的研究结果有助于增进对抑郁症病理生理学的理解。
