Kurhe Yeshwant, Mahesh Radhakrishnan
Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
Indian J Pharmacol. 2017 Jul-Aug;49(4):290-296. doi: 10.4103/ijp.IJP_805_16.
Obesity is an important risk factor for depression as more than half of the obese population is susceptible for depression at double rate. Our earlier studies reported the antidepressant potential of 5-HT receptor antagonist, ondansetron (OND) in depression associated obesity using behavioral tasks. The present research work is aimed to evaluate the effect of OND on depression associated with obesity with special emphasis on biochemical and molecular mechanisms such as hippocampal brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP), 5-hydroxytryptamine (5-HT), hippocampal histological examination and immunohistochemical expression of p53 proteins.
Mice were fed with high-fat diet (HFD) for 14 weeks, followed by treatment schedule for 28 days with vehicle/OND (0.5 and 1 mg/kg, p.o.)/reference antidepressant escitalopram (10 mg/kg, p.o.). Subsequently, animals were screened in the behavioral tests of depression such as forced swim test (FST) and sucrose preference test (SPT), biochemical estimations including hippocampal cAMP, BDNF and 5-HT, and molecular assays mainly histology and p53 expression of dentate gyrus (DG).
HFD-fed mice showed increased immobility time in FST, reduced sucrose consumption in SPT, decreased level of signal transduction factor cAMP, neuronal growth factor BDNF and neurotransmitter 5-HT in the hippocampus, and raised and p53 expression neuronal damage in the DG region of mice fed with HFD in comparison to the mice fed with normal pellet diet. Chronic treatment with OND (0.5 and 1 mg/kg, p.o.) significantly inhibited the behavioral, biochemical and molecular modifications in HFD-fed mice.
In the preliminary study, OND attenuated depression associated with obesity in mice fed with HFD using various assays procedures, at least in part by the modulation of serotonergic transmission.
肥胖是抑郁症的一个重要风险因素，因为超过一半的肥胖人群患抑郁症的几率是正常人的两倍。我们早期的研究报告了5-羟色胺（5-HT）受体拮抗剂昂丹司琼（OND）在与肥胖相关的抑郁症中，通过行为任务表现出的抗抑郁潜力。本研究旨在评估OND对与肥胖相关的抑郁症的影响，特别关注生物化学和分子机制，如海马脑源性神经营养因子（BDNF）、环磷酸腺苷（cAMP）、5-羟色胺（5-HT）、海马组织学检查以及p53蛋白的免疫组化表达。
给小鼠喂食高脂饮食（HFD）14周，随后用溶剂/OND（0.5和1毫克/千克，口服）/参考抗抑郁药艾司西酞普兰（10毫克/千克，口服）进行28天的治疗。随后，对动物进行抑郁症行为测试，如强迫游泳试验（FST）和蔗糖偏好试验（SPT），进行生物化学评估，包括海马cAMP、BDNF和5-HT，以及分子分析，主要是齿状回（DG）的组织学和p53表达。
与喂食正常颗粒饲料的小鼠相比，喂食HFD的小鼠在FST中不动时间增加，在SPT中蔗糖消耗量减少，海马中信号转导因子cAMP、神经营养因子BDNF和神经递质5-HT水平降低，并且喂食HFD的小鼠DG区域神经元损伤和p53表达增加。用OND（0.5和1毫克/千克，口服）进行慢性治疗可显著抑制喂食HFD小鼠的行为、生物化学和分子变化。
在初步研究中，OND使用各种检测程序减轻了喂食HFD小鼠与肥胖相关的抑郁症，至少部分是通过调节5-羟色胺能传递实现的。
