D5 receptor agonist 027075 promotes cognitive function recovery and neurogenesis in a Aβ1-42-induced mouse model
D5 receptor agonist 027075 promotes cognitive function recovery and neurogenesis in a Aβ1-42-induced mouse model
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DOI：
10.1016/j.neuropharm.2016.01.008
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发表时间：
2016-06-01
影响因子：
4.7
通讯作者：
He, Ling
中科院分区：
文献类型：
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作者：
Shen, Ling;Yan, Ming;He, Ling
在这项研究中，建立了一个高通量筛选系统，以确定D5受体激动剂-027075。采用Morris水迷宫、被动回避、主动回避、旷场和跳台等行为学试验评价027075对A β（1-42）诱导小鼠的保护作用。通过体外高含量筛选评估027075的神经保护作用。在行为测试中，027075以剂量依赖性方式显著改善A β（1-42）引起的认知功能损害。027075（8 mg/kg）能显著延长Morris水迷宫实验中大鼠在目标象限内停留的时间。与模型组相比，被动回避任务和跳台实验的潜伏期明显延长，错误次数明显减少。027075（8 mg/kg）可显著缩短主动回避和旷场实验的潜伏期、刺激时间、错误次数，增加回避次数、穿越直线次数和中心距离。与027075-H（8 mg/kg）相比，027075-H + SCH 39166（5 mg/kg）显著逆转了上述所有结果。027075的神经保护作用通过促进细胞分化和延长神经突长度来证明。D1/D5受体拮抗剂SCH 39166可阻断上述作用。这些结果表明，D5受体可能是治疗AD的理想靶点，其激动剂有可能成为未来AD的新药物。(C)2016爱思唯尔有限公司版权所有。
In this study, a high throughput screening system was set up to identify D5 receptor agonists-027075. Then, a series of behavior tests were used to evaluate the beneficial effects of 027075 in A beta(1-42)-induced mice model including morris water maze, passive avoidance, active avoidance, open field and step-down test. The neuroprotective effect of 027075 was assessed by a high content screening in vitro. In behavior tests, the cognitive function impairment caused by A beta(1-42) was significantly ameliorated by 027075 in a dose-dependent manner. 027075 (8 mg/kg) significantly prolonged the time spent in the target quadrant when compared to the model group in morris water maze test. The latency was significantly increased and the number of errors was decreased in both passives avoidance task and step down test when compared to the model group. In active avoidance and open field test, latency, stimulation time, number of errors were significantly reduced, while number of avoidance and line crossing and central distance were increased by 027075 (8 mg/kg). All the results above was significantly reversed by 027075-H + SCH39166 (5 mg/kg) when compared to 027075-H (8 mg/kg). The neuroprotective effect of 027075 was demonstrated by promotion of cell differentiation and extension of neurite length. But the effects were abrogated by the specific D1/D5 antagonist, SCH39166. These results indicate that D5 receptor might be used as an ideal target for the treatment of AD and its agonists might become a new AD drugs in the future. (C) 2016 Elsevier Ltd. All rights reserved.