Yu Ruixue, Yang Wenqing, Qi Dongmei, Gong Lili, Li Chao, Li Yunlun, Jiang Haiqiang
School of Pharmaceutical Sciences, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine Jinan 250355 China
Experience Center of Shandong University of Traditional Chinese Medicine Jinan 250355 Shandong China
RSC Adv. 2019 Jul 26;9(40):23276-23288. doi: 10.1039/c9ra02377a. eCollection 2019 Jul 23.
Essential hypertension (EH) is a prevalent chronic medical condition and a major risk factor for cardiovascular morbidity and mortality. Neurotransmitters are involved in the physiological process of blood pressure regulation in the body. Studies have shown that oleanolic acid (OA) can effectively regulate neurotransmitter-related metabolic disorders caused by EH, but the mechanism is still unclear. Here, we studied the neurotransmitter metabolic profiles in five brain regions by targeted metabolomics approaches in spontaneously hypertensive rats (SHRs) treated with OA and vehicle. Samples from five brain regions (hippocampus, striatum, hypothalamus, temporal lobe, and frontal lobe) were collected from the control group, the spontaneously hypertensive rat (SHR) group, and the OA group. Targeted metabolomics based on UPLC-Q-Exactive-MS was employed to characterize the dramatically changed neurotransmitters in the brain regions of SHRs treated with OA and vehicle. The expressions of the key enzymes involved in the neurotransmitter metabolism were detected by the reverse transcription-polymerase chain reaction (RT-PCR). The metabolomic profiles of SHRs pre-protected by OA were significantly different from those of unprotected SHRs. A total of 18 neurotransmitters could be confirmed as significantly altered metabolites, which were involved in tyrosine and glutamate metabolism as well as other pathways. The results showing seven key enzymes in neurotransmitter metabolism further validated the changes in the metabolic pathways. OA could effectively restore tyrosine metabolism in the striatum and hypothalamus, glutamate metabolism in the hippocampus, striatum and temporal lobe, cholinergic metabolism in the striatum, and histidine metabolism in the hypothalamus due to its inhibition of inflammatory reactions, structural damage of the neuronal cells, and increase in sedative activity. This study indicated that brain region-targeted metabolomics can provide a powerful tool to further investigate the possible mechanism of OA in EH.
原发性高血压（EH）是一种常见的慢性疾病，也是心血管疾病发病和死亡的主要危险因素。神经递质参与人体血压调节的生理过程。研究表明，齐墩果酸（OA）可有效调节由EH引起的神经递质相关代谢紊乱，但其机制仍不清楚。在此，我们通过靶向代谢组学方法研究了用OA和赋形剂处理的自发性高血压大鼠（SHR）五个脑区的神经递质代谢谱。从对照组、自发性高血压大鼠（SHR）组和OA组收集五个脑区（海马体、纹状体、下丘脑、颞叶和额叶）的样本。采用基于超高效液相色谱-四极杆-静电场轨道阱质谱（UPLC-Q-Exactive-MS）的靶向代谢组学方法来表征用OA和赋形剂处理的SHR脑区中显著变化的神经递质。通过逆转录-聚合酶链反应（RT-PCR）检测神经递质代谢中关键酶的表达。经OA预处理的SHR的代谢组学谱与未预处理的SHR有显著差异。共有18种神经递质可被确认为显著改变的代谢物，它们参与酪氨酸和谷氨酸代谢以及其他途径。显示神经递质代谢中七种关键酶的结果进一步验证了代谢途径的变化。OA可通过抑制炎症反应、神经元细胞结构损伤和增加镇静活性，有效恢复纹状体和下丘脑的酪氨酸代谢、海马体、纹状体和颞叶的谷氨酸代谢、纹状体的胆碱能代谢以及下丘脑的组氨酸代谢。本研究表明，脑区靶向代谢组学可为进一步研究OA在EH中的可能机制提供有力工具。
