Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
Brain Behav Immun. 2018 Mar;69:386-398. doi: 10.1016/j.bbi.2017.12.013. Epub 2017 Dec 27.
Hyperammonemia is a main contributor to cognitive impairment and motor in-coordination in patients with hepatic encephalopathy. Hyperammonemia-induced neuroinflammation mediates the neurological alterations in hepatic encephalopathy. Intracerebral administration of extracellular cGMP restores some but not all types of cognitive impairment. Motor in-coordination, is mainly due to increased GABAergic tone in cerebellum. We hypothesized that extracellular cGMP would restore motor coordination in hyperammonemic rats by normalizing GABAergic tone in cerebellum and that this would be mediated by reduction of neuroinflammation. The aims of this work were to assess whether chronic intracerebral administration of cGMP to hyperammonemic rats: 1) restores motor coordination; 2) reduces neuroinflammation in cerebellum; 3) reduces extracellular GABA levels and GABAergic tone in cerebellum; and also 4) to provide some advance in the understanding on the molecular mechanisms involved. The results reported show that rats with chronic hyperammonemia show neuroinflammation in cerebellum, including microglia and astrocytes activation and increased levels of IL-1b and TNFa and increased membrane expression of the TNFa receptor. This is associated with increased glutaminase expression and extracellular glutamate, increased amount of the GABA transporter GAT-3 in activated astrocytes, increased extracellular GABA in cerebellum and motor in-coordination. Chronic intracerebral administration of extracellular cGMP to rats with chronic hyperammonemia reduces neuroinflammation, including microglia and astrocytes activation and membrane expression of the TNFa receptor. This is associated with reduced nuclear NF-κB, glutaminase expression and extracellular glutamate, reduced amount of the GABA transporter GAT-3 in activated astrocytes and reduced extracellular GABA in cerebellum and restoration of motor coordination. The data support that extracellular cGMP restores motor coordination in hyperammonemic rats by reducing microglia activation and neuroinflammation, leading to normalization of extracellular glutamate and GABA levels in cerebellum and of motor coordination.
高氨血症是肝性脑病患者认知障碍和运动不协调的主要原因。高氨血症诱导的神经炎症介导肝性脑病的神经改变。脑室内给予细胞外 cGMP 可恢复部分但不是所有类型的认知障碍。运动不协调主要是由于小脑 GABA 能张力增加。我们假设，细胞外 cGMP 通过使小脑 GABA 能张力正常化来恢复高氨血症大鼠的运动协调性，并且这将通过减少神经炎症来介导。这项工作的目的是评估慢性脑室内给予 cGMP 是否可以使高氨血症大鼠：1）恢复运动协调性；2）降低小脑的神经炎症；3）降低小脑的细胞外 GABA 水平和 GABA 能张力；并为理解涉及的分子机制提供一些进展。报告的结果表明，慢性高氨血症大鼠小脑存在神经炎症，包括小胶质细胞和星形胶质细胞激活以及白细胞介素-1b 和肿瘤坏死因子-a 水平升高以及肿瘤坏死因子-a 受体的膜表达增加。这与谷氨酰胺酶表达增加和细胞外谷氨酸增加、激活的星形胶质细胞中 GABA 转运体 GAT-3 的含量增加、小脑细胞外 GABA 增加和运动不协调有关。慢性脑室内给予细胞外 cGMP 可降低慢性高氨血症大鼠的神经炎症，包括小胶质细胞和星形胶质细胞激活以及肿瘤坏死因子-a 受体的膜表达。这与核 NF-κB、谷氨酰胺酶表达和细胞外谷氨酸减少、激活的星形胶质细胞中 GABA 转运体 GAT-3 的含量减少以及小脑细胞外 GABA 减少和运动协调性恢复有关。数据支持细胞外 cGMP 通过减少小胶质细胞激活和神经炎症来恢复高氨血症大鼠的运动协调性，从而使小脑细胞外谷氨酸和 GABA 水平以及运动协调性正常化。
