Fu Wan, Xie Heng, Laudon Moshe, Zhou Shouhong, Tian Shaowen, You Yong
Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People's Republic of China.
Neurim Pharmaceuticals Ltd., Tel-Aviv, Israel.
Psychopharmacology (Berl). 2016 Jun;233(12):2229-39. doi: 10.1007/s00213-016-4272-3. Epub 2016 Mar 23.
Previous studies have demonstrated that piromelatine (a melatonin and serotonin 5-HT1A and 5-HT1D agonist) exerts an antidepressant activity in rodent models of acute stress and improves cognitive impairments in a rat model of Alzheimer's disease (AD). However, the role of piromelatine in chronic stress-induced memory dysfunction remains unclear.
The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms.
Rats were exposed randomly to chronic mild stressors for 7 weeks to induce anhedonia (reflected by a significant decrease in sucrose intake), which was used to select rats vulnerable (CMS-anhedonic, CMSA) or resistant (CMS-resistant, CMSR) to stress. Piromelatine (50 mg/kg) was administered daily during the last 2 weeks of CMS. The tail suspension and forced swimming tests were adopted to further characterize vulnerable and resilient rats. The Y-maze and novel object recognition (NOR) tests were used to evaluate memory performance. Brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB), and cytogenesis were measured in the hippocampus.
We found that only CMSA rats displayed significant increases in immobility time in the tail suspension and forced swimming tests; memory deficits in the Y-maze and NOR tests; significant decreases in hippocampal BDNF, CREB, and pCREB expression; and cytogenesis. All these anhedonia-associated effects were reversed by piromelatine.
Piromelatine ameliorates memory deficits associated with CMS-induced anhedonia in rats and this effect may be mediated by restoring hippocampal BDNF, CREB, and cytogenesis deficits.
先前的研究表明，吡咯美汀（一种褪黑素及5-羟色胺5-HT1A和5-HT1D激动剂）在急性应激的啮齿动物模型中发挥抗抑郁活性，并改善阿尔茨海默病（AD）大鼠模型的认知障碍。然而，吡咯美汀在慢性应激诱导的记忆功能障碍中的作用仍不清楚。
本研究旨在确定吡咯美汀是否能改善慢性轻度应激（CMS）诱导的记忆缺陷，并探究其潜在机制。
将大鼠随机暴露于慢性轻度应激源7周以诱导快感缺失（通过蔗糖摄入量显著降低来反映），以此选择对压力敏感（CMS-快感缺失，CMSA）或有抗性（CMS-抗性，CMSR）的大鼠。在CMS的最后2周每天给予吡咯美汀（50mg/kg）。采用悬尾试验和强迫游泳试验进一步表征敏感和有恢复力的大鼠。使用Y迷宫试验和新物体识别（NOR）试验评估记忆表现。测量海马中脑源性神经营养因子（BDNF）、环磷腺苷效应元件结合蛋白（CREB）、磷酸化CREB（pCREB）和细胞生成情况。
我们发现，只有CMSA大鼠在悬尾试验和强迫游泳试验中的不动时间显著增加；在Y迷宫试验和NOR试验中存在记忆缺陷；海马中BDNF、CREB和pCREB表达显著降低；以及细胞生成减少。吡咯美汀可逆转所有这些与快感缺失相关的效应。
吡咯美汀可改善大鼠中与CMS诱导的快感缺失相关的记忆缺陷，且这种作用可能是通过恢复海马BDNF、CREB和细胞生成缺陷来介导的。
