Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mol Neurobiol. 2020 Aug;57(8):3552-3567. doi: 10.1007/s12035-020-01985-4. Epub 2020 Jun 15.
Astrocytes are functionally diverse glial cells that maintain blood-brain barrier (BBB) integrity, provide metabolic and trophic support, and react to pathogens or harmful stimuli through inflammatory response. Impairment of astrocyte functions has been implicated in hepatic encephalopathy (HE), a neurological complication associated with hyperammonemia. Although hyperammonemia is more common in adults, ammonia gliotoxicity has been mainly studied in cultured astrocytes derived from neonate animals. However, these cells can sense and respond to stimuli in different ways from astrocytes obtained from adult animals. Thus, the aim of this study was to investigate the direct effects of ammonia on astrocyte cultures obtained from adult rats compared with those obtained from neonate rats. Our main findings pointed that ammonia increased the gene expression of proteins associated with BBB permeability, in addition to cause an inflammatory response and decrease the release of trophic factors, which were dependent on p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor κB (NFκB) pathways and aquaporin 4, in both neonatal and mature astrocytes. Considering the age, mature astrocytes presented an overall increase of the expression of inflammatory signaling components and a decrease of the expression of cytoprotective pathways, compared with neonatal astrocytes. Importantly, ammonia exposure in mature astrocytes potentiated the expression of the senescence marker p21, inflammatory response, activation of p38 MAPK/NFκB pathways, and the decrease of cytoprotective pathways. In this regard, ammonia can trigger and/or accelerate the inflammaging of mature astrocytes, a phenomenon characterized by an age-related chronic and low-grade inflammation, which may be implicated in HE neurological symptoms.
星形胶质细胞是功能多样的神经胶质细胞，它们维持血脑屏障（BBB）的完整性，提供代谢和营养支持，并通过炎症反应对病原体或有害刺激作出反应。星形胶质细胞功能障碍与肝性脑病（HE）有关，HE 是一种与血氨升高相关的神经并发症。尽管高氨血症在成人中更为常见，但氨的神经毒性主要在源自新生动物的培养星形胶质细胞中进行研究。然而，这些细胞在感知和响应刺激方面与成年动物来源的星形胶质细胞不同。因此，本研究旨在比较成年大鼠和新生大鼠来源的星形胶质细胞培养物中氨的直接作用。我们的主要发现表明，氨增加了与 BBB 通透性相关的蛋白的基因表达，此外还引起炎症反应并减少了营养因子的释放，这依赖于 p38 丝裂原活化蛋白激酶（p38 MAPK）/核因子 κB（NFκB）途径和水通道蛋白 4，在新生和成熟星形胶质细胞中均如此。考虑到年龄因素，与新生星形胶质细胞相比，成熟星形胶质细胞表现出炎症信号成分的整体表达增加和细胞保护途径的表达减少。重要的是，氨暴露在成熟星形胶质细胞中增强了衰老标志物 p21 的表达、炎症反应、p38 MAPK/NFκB 途径的激活以及细胞保护途径的减少。在这方面，氨可以触发和/或加速成熟星形胶质细胞的衰老炎症，这是一种与年龄相关的慢性低度炎症现象，可能与 HE 的神经症状有关。
