Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
Protein Pept Lett. 2022;29(12):1042-1050. doi: 10.2174/0929866529666220825150025.
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that involves cognitive and motor dysfunctions due to hepatic failure. The clinical and experimental studies suggest that the angiotensin (Ang) converting enzyme (ACE), Ang II, and angiotensin type 1 receptor (AT1R), which compose the classical pathway of the renin-angiotensin system (RAS), exacerbate neuroinflammation in different neurologic diseases. Conversely, Ang-(1-7), ACE2, and Mas receptor, which integrate the alternative RAS axis, have been shown as promising therapeutic targets in neuropsychiatric disorders, leading to neuroprotection.
This study aimed to investigate the potential participation of the RAS components in thioacetamide (TAA)-induced HE in mice.
We also evaluated the levels of neurotrophic factors, pro-inflammatory cytokines, and chemokine in the central nervous system of TAA-induced HE in mice. Mice were submitted to acute liver failure induced by TAA administration by intraperitoneal route. Measurements of RAS components (ACE, Ang II, ACE2 and Ang1-7) and neurotrophic factors (BDNF, GDNF and NGF) were obtained by ELISA assay. Pro-inflammatory cytokines (TNF, IFN-γ, IL-6, IL-12p70) and the chemokine (CCL2) were quantified by cytometric bead array. The student's t-test was applied for statistical analysis.
Mice presented increased cortical levels of ACE, while Ang-(1-7) levels were decreased in cortical and hippocampal samples compared to controls. Moreover, HE mice had an increase in the Ang II/Ang-(1-7) ratio along with reduced levels of neural growth factor (NGF) in the prefrontal cortex. They also showed elevated levels of IFN-γ and CCL2 in the prefrontal cortex and of TNF, IL-6, IL-12, and CCL2 in the hippocampus compared with controls.
This study suggested that the reduction of components of the alternative RAS axis was associated with the deleterious effects of neuroinflammation and lower neuroprotective effects of NGF during TAA-induced HE.
肝性脑病（HE）是一种涉及认知和运动功能障碍的神经精神综合征，由肝功能衰竭引起。临床和实验研究表明，血管紧张素（Ang）转换酶（ACE）、血管紧张素 II（Ang II）和血管紧张素 1 型受体（AT1R），它们构成了肾素-血管紧张素系统（RAS）的经典途径，在不同的神经疾病中加剧神经炎症。相反，血管紧张素-（1-7）、ACE2 和 Mas 受体，整合了替代的 RAS 轴，已被证明是神经精神疾病有希望的治疗靶点，导致神经保护。
本研究旨在探讨 RAS 成分在硫代乙酰胺（TAA）诱导的小鼠 HE 中的潜在作用。
我们还评估了 TAA 诱导的 HE 小鼠中枢神经系统中神经营养因子、促炎细胞因子和趋化因子的水平。通过腹腔途径给予 TAA 诱导急性肝衰竭，测量 RAS 成分（ACE、Ang II、ACE2 和 Ang1-7）和神经营养因子（BDNF、GDNF 和 NGF）。通过流式细胞术检测促炎细胞因子（TNF、IFN-γ、IL-6、IL-12p70）和趋化因子（CCL2）的含量。采用学生 t 检验进行统计学分析。
与对照组相比，小鼠皮质 ACE 水平升高，而皮质和海马样本中 Ang-（1-7）水平降低。此外，HE 小鼠前额叶皮质中的 Ang II/Ang-（1-7）比值增加，神经生长因子（NGF）水平降低。与对照组相比，它们在前额叶皮质中还表现出 IFN-γ和 CCL2 水平升高，在海马中表现出 TNF、IL-6、IL-12 和 CCL2 水平升高。
本研究表明，替代 RAS 轴的组成部分减少与神经炎症的有害影响以及 TAA 诱导的 HE 期间 NGF 的神经保护作用降低有关。
