Yang Nan, Ren Zhili, Zheng Ji, Feng Lu, Li Dongmei, Gao Kai, Zhang Lianfeng, Liu Yanyong, Zuo Pingping
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.
Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China.
Neuropharmacology. 2016 Jun;105:587-593. doi: 10.1016/j.neuropharm.2016.02.031. Epub 2016 Feb 27.
Most current pharmacologic antidepressant treatments target monoaminergic systems confronts some problems such as low rate of remission and high risk for relapse indicating new therapeutic strategy is urgently need. Evidences showed that impairments in mitochondrial function were associated with the pathogenesis of mood disorders and improvement in its function may be a novel therapeutic choice. In the present study, effects of 5-(4-hydroxy-3-dimethoxybenzylidene)-2-thioxo-4-thiazolidinone (RD-1) were investigated in mice model of depression/anxiety induced by corticosterone (20 mg/kg) subcutaneously repeated injections in 5-week male BALB/c mice. Our results showed that five weeks of corticosterone administration induced anxiety/depressive-like behavioral changes, including decreased central activities in open field test, increased the immobility time in forced swimming test and the latency in the novelty-suppressed feeding test, as well as reduced bodyweight. Results showed that oral administration with RD-1 at the doses of 25, 50, and 100 mg/kg for five weeks significantly improved the anxiety/depressive-like behavioral changes induced by corticosterone. In glucose metabolism analysis by photon emission computed tomography/-computed tomography (PET/CT) imaging, corticosterone significantly deactivated the prefrontal cortex (PFC), temporal lobe and hippocampus. RD-1 treatment obviously improved the energy metabolism in the involved brain regions. In primary cultured hippocampal neuron, corticosterone reduced speed of anterograde transport, yet speed of retrograde transport was increased. Furthermore, RD-1 enhanced the mitochondrial anterograde transport to supply energy for the neurotransmitter release. In conclusion, RD-1 prevents anxiety/depressive-like behavior of mice induced by corticosterone repeated injections with novel mechanism of improvement in the mitochondrial function.
目前大多数抗抑郁药物治疗都针对单胺能系统，但面临一些问题，如缓解率低和复发风险高，这表明迫切需要新的治疗策略。有证据表明，线粒体功能受损与情绪障碍的发病机制有关，改善其功能可能是一种新的治疗选择。在本研究中，我们在5周龄雄性BALB/c小鼠皮下重复注射皮质酮（20mg/kg）诱导的抑郁/焦虑小鼠模型中研究了5-(4-羟基-3-二甲氧基苄叉)-2-硫代-4-噻唑烷酮（RD-1）的作用。我们的结果表明，连续5周给予皮质酮会诱导焦虑/抑郁样行为改变，包括旷场试验中自主活动减少、强迫游泳试验中不动时间增加、新奇抑制摄食试验中潜伏期延长以及体重减轻。结果显示，以25、50和100mg/kg的剂量口服RD-1 5周可显著改善皮质酮诱导的焦虑/抑郁样行为改变。在通过正电子发射断层扫描/计算机断层扫描（PET/CT）成像进行的葡萄糖代谢分析中，皮质酮显著使前额叶皮质（PFC）、颞叶和海马失活。RD-1治疗明显改善了相关脑区的能量代谢。在原代培养的海马神经元中，皮质酮降低了顺行运输速度，但逆行运输速度增加。此外，RD-1增强了线粒体顺行运输，为神经递质释放提供能量。总之，RD-1通过改善线粒体功能的新机制预防了皮质酮重复注射诱导的小鼠焦虑/抑郁样行为。
