Wan Fu1, Heng Xie1, Moshe Laudon2, Shouhong Zhou3,4, Shaowen Tian5,6, Yong You7. 1. Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People's Republic of China. 2. Neurim Pharmaceuticals Ltd., Tel-Aviv, Israel. 3. Department of Physiology, Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China. 4. Institute of Neuroscience, College of Medicine, University of South China, Hengyang, Hunan, 421001, People's Republic of China. 5. Department of Physiology, Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China. tsw.neuro@126.com. 6. Institute of Neuroscience, College of Medicine, University of South China, Hengyang, Hunan, 421001, People's Republic of China. tsw.neuro@126.com. 7. Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People's Republic of China. youyong2000@126.com.
Abstract
RATIONALE: 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. OBJECTIVE: The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
RATIONALE: Previous studies have demonstrated that piromelatine (a melatonin and serotonin5-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. OBJECTIVE: The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms. METHODS: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. RESULTS: 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. CONCLUSIONS: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.
Authors: Maurizio Fava; Steven D Targum; Andrew A Nierenberg; Leo S Bleicher; Todd A Carter; Pamela C Wedel; René Hen; Fred H Gage; Carrolee Barlow Journal: J Psychiatr Res Date: 2012-09-19 Impact factor: 4.791