Laboratory of Functional Neuromorphology, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska Str. 3, 83306 Bratislava, Slovak Republic.
Neurochem Int. 2011 Nov;59(6):889-95. doi: 10.1016/j.neuint.2011.08.001. Epub 2011 Aug 6.
Many peripheral substances, including ghrelin, induce neuronal activation in the brain. In the present study, we compared the effect of subcutaneously administered ghrelin and its three stable agonists: Dpr(3)ghr ([Dpr(N-octanoyl)(3)] ghrelin) (Dpr - diaminopropionic acid), YA GHRP-6 (H-Tyr-Ala-His-DTrp-Ala-Trp-DPhe-Lys-NH(2)), and JMV1843 (H-Aib-DTrp-D-gTrp-CHO) on the Fos expression in food intake-responsive brain areas such as the hypothalamic paraventricular (PVN) and arcuate (ARC) nuclei, the nucleus of the solitary tract (NTS), and area postrema (AP) in male C57BL/6 mice. Immunohistochemical analysis showed that acute subcutaneous dose of each substance (5mg/kg b.w.), which induced a significant food intake increase, elevated Fos protein expression in all brain areas studied. Likewise ghrelin, each agonist tested induced distinct Fos expression overall the PVN. In the ARC, ghrelin and its agonists specifically activated similarly distributed neurons. Fos occurrence extended from the anterior (aARC) to middle (mARC) ARC region. In the latter part of the ARC, the Fos profiles were localized bilaterally, especially in the ventromedial portions of the nucleus. In the NTS, all substances tested also significantly increased the number of Fos profiles in neurons, which also revealed specific location, i.e., in the NTS dorsomedial subnucleus (dmNTS) and the area subpostrema (AsP). In addition, cells located nearby the NTS, in the AP, also revealed a significant increase in number of Fos-activated cells. These results demonstrate for the first time that ghrelin agonists, regardless of their different chemical nature, have a significant and similar activating impact on specific groups of neurons that can be a part of the circuits involved in the food intake regulation. Therefore there is a real potency for ghrelin agonists to treat cachexia and food intake disorders. Thus, likewise JMV1843, the other ghrelin agonists represent substances that might be involved in trials for clinical purposes.
许多外周物质，包括胃饥饿素，会诱导大脑中的神经元激活。在本研究中，我们比较了皮下给予胃饥饿素及其三种稳定类似物：Dpr(3)ghr[Dpr（N-辛酰基）（3）]胃饥饿素（Dpr-二氨基丙酸）、YA GHRP-6（H-Tyr-Ala-His-DTrp-Ala-Trp-DPhe-Lys-NH2）和 JMV1843（H-Aib-DTrp-D-gTrp-CHO）对雄性 C57BL/6 小鼠进食反应性脑区（如下丘脑室旁核（PVN）和弓状核（ARC）、孤束核（NTS）和最后区（AP））中 Fos 表达的影响。免疫组织化学分析显示，每种物质（5mg/kg b.w.）的急性皮下剂量均能显著增加食物摄入，并增加了所有研究脑区的 Fos 蛋白表达。与胃饥饿素一样，测试的每种激动剂都在整个 PVN 中诱导了不同的 Fos 表达。在 ARC 中，胃饥饿素及其激动剂特异性地激活了分布相似的神经元。Fos 发生从 ARC 的前部（aARC）延伸到中部（mARC）区域。在 ARC 的后部分，Fos 图谱定位在双侧，特别是核的腹内侧部分。在 NTS 中，测试的所有物质也显著增加了神经元中 Fos 图谱的数量，这些图谱也显示了特定的位置，即在 NTS 背内侧亚核（dmNTS）和亚最后区（AsP）。此外，位于 NTS 附近的 AP 中的细胞也显示出 Fos 激活细胞数量的显著增加。这些结果首次表明，胃饥饿素激动剂，无论其化学性质如何不同，对特定神经元群具有显著且相似的激活作用，这些神经元群可能是参与食物摄入调节的回路的一部分。因此，胃饥饿素激动剂具有治疗恶病质和食物摄入障碍的真正潜力。因此，与 JMV1843 一样，其他胃饥饿素激动剂代表了可能参与临床试验的物质。
