Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou, China; The Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand; Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1124, New Zealand; Brain Research New Zealand, A Centre of Research Excellence, New Zealand.
The Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand; Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1124, New Zealand; Brain Research New Zealand, A Centre of Research Excellence, New Zealand.
Neuropeptides. 2019 Aug;76:101935. doi: 10.1016/j.npep.2019.05.006. Epub 2019 May 22.
Childhood metabolic disorders are associated with insulin-like growth factor (IGF)-1 deficiency, which can adversely affect brain development and function. As a neuropeptide, cyclic glycine-proline (cGP) improves IGF-1 function in brain and regulates IGF-1 bioavailability in plasma. Whether such a regulatory process mediates the neurotrophic effects of cGP remains unknown. This study examined the effects cGP treatment on synaptic expression and their association with IGF-1, IGF binding protein (IGFBP)-2 and cGP concentrations in the brain of rats with high fat diet (HFD)-induced obesity. Male rats received either a HFD or a standard chow diet (STD) from weaning and were then treated with either saline or cGP from 11 to 15 weeks of age. The concentrations of cGP, IGF-1 and IGFBP-2 were measured in the brain tissues using ELISA and HPLC-MS. The expressions of synaptic markers were evaluated in the hippocampus, hypothalamus and striatum using immunohistochemical staining. Compared to the STD group, IGF-1 and IGFBP-2, but not cGP concentrations, were lower in the HFD groups. The expression of hippocampal synaptophysin, glutamate receptor-1, GFAP and striatal tyrosine-hydroxylase were also reduced in the HFD groups. While treatment did not alter tissue IGF-1, cGP administration that increased the concentration of cGP in brain tissues, normalized the expression of synaptophysin, GFAP and tyrosine-hydroxylase, but not glutamate receptor-1. IGF-1 concentration in brain tissues correlated with the expression of all synaptic markers. HFD feeding reduced synaptic expression and tissue IGF-1 in brains which were closely associated, thus suggesting IGF-1 in the brain is largely bioavailable. Without increasing IGF-1 in the brain, administration of cGP normalized synaptic expression, possibly be mediated through increasing bioavailable IGF-1, but further studies are required to confirm this.
儿童代谢紊乱与胰岛素样生长因子 (IGF)-1 缺乏有关，这会对大脑发育和功能产生不利影响。作为一种神经肽，环状甘氨酸-脯氨酸 (cGP) 可改善大脑中的 IGF-1 功能，并调节血浆中 IGF-1 的生物利用度。这种调节过程是否介导 cGP 的神经营养作用尚不清楚。本研究探讨了 cGP 治疗对高脂肪饮食 (HFD) 诱导肥胖大鼠大脑中突触表达的影响及其与 IGF-1、IGF 结合蛋白 (IGFBP)-2 和 cGP 浓度的关系。雄性大鼠从断奶开始分别给予 HFD 或标准 chow 饮食 (STD)，然后在 11 至 15 周龄时分别用生理盐水或 cGP 治疗。使用 ELISA 和 HPLC-MS 测量脑组织中 cGP、IGF-1 和 IGFBP-2 的浓度。使用免疫组织化学染色评估海马体、下丘脑和纹状体中的突触标志物表达。与 STD 组相比，HFD 组 IGF-1 和 IGFBP-2 浓度降低，而 cGP 浓度无差异。HFD 组海马突触素、谷氨酸受体-1、GFAP 和纹状体酪氨酸羟化酶的表达也减少。虽然治疗并未改变组织 IGF-1，但增加脑组织中 cGP 浓度的 cGP 给药可使突触素、GFAP 和酪氨酸羟化酶的表达正常化，但谷氨酸受体-1 表达未改变。脑组织中 IGF-1 浓度与所有突触标志物的表达相关。HFD 喂养降低了大脑中的突触表达和组织 IGF-1，这两者密切相关，因此表明大脑中的 IGF-1 具有很大的生物利用度。在不增加大脑中的 IGF-1 的情况下，cGP 的给药可使突触表达正常化，这可能是通过增加生物利用度的 IGF-1 介导的，但需要进一步的研究来证实这一点。
