Cognitive enhancing effects of ghrelin receptor agonists
Cognitive enhancing effects of ghrelin receptor agonists
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DOI：
10.1007/s00213-009-1620-6
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发表时间：
2009-10-01
影响因子：
3.4
通讯作者：
Pemberton, Darrel J.
中科院分区：
文献类型：
--
作者：
Atcha, Zeenat;Chen, Woei-Shin;Pemberton, Darrel J.
生长激素促分泌素受体的内源性配体Ghrelin在多种生理过程中发挥作用，包括食欲调节、新陈代谢和最近的树突棘构筑、长时程增强和认知。本研究的目的是确定两种结构上的非肽Ghrelin受体激动剂(GSK894490A和CP-464709-18)对啮齿动物认知的影响。测试化合物对大鼠认知能力的影响是通过新的物体识别测试、改进的水迷宫范式和东莨菪碱诱导的线索恐惧条件反射缺陷来确定的。之所以选择这些测试，是因为它们都探测了一个相对独立的认知域，因此可能具有不同的潜在神经基础。这两种化合物在新的物体识别和改进的水迷宫测试中都显著提高了表现，但无法减弱提示恐惧条件下的东莨菪碱缺乏。这些结果表明，这里描述的小分子Ghrelin受体激动剂很容易跨越血/脑屏障，并在识别和空间学习和记忆测试中引发前认知效应。基于这些观察，中枢Ghrelin受体似乎是一种化学上易于处理的受体，也许应该被视为治疗影响认知的疾病的治疗方法的新药物靶点。
Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been shown to play a role in multiple physiological processes including appetite regulation, metabolism and, more recently, dendritic spine architecture, long-term potentiation and cognition.The objective of this study was to determine the effects of two structurally non-peptide ghrelin receptor agonists (GSK894490A and CP-464709-18) on rodent cognition.All experiments were performed in male Lister hooded rats. Effects of the test compounds on rat cognitive performance was determined using the novel object recognition test, a modified water maze paradigm and a scopolamine-induced deficit in cued fear conditioning. These tests were chosen as they each probe a relatively independent cognitive domain and therefore potentially have differing underlying neural substrates.Both compounds significantly improved performance in the novel object recognition and modified water maze tests but were unable to attenuate a scopolamine deficit in cued fear conditioning.These results demonstrate that the small-molecule ghrelin receptor agonists profiled here readily cross the blood/brain barrier and elicit pro-cognitive effects in recognition and spatial learning and memory tests. Based on these observations, the central ghrelin receptor would appear to be a chemically tractable receptor and perhaps should be considered as a new drug target for therapeutic approaches to treat diseases affecting cognition.