Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain.
Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular, Centro Investigación Príncipe Felipe/Universidad Católica de Valencia Valencia, Spain.
J Hepatol. 2020 Sep;73(3):582-592. doi: 10.1016/j.jhep.2019.01.008. Epub 2019 Jan 14.
BACKGROUND & AIMS: Chronic hyperammonemia induces neuroinflammation which mediates cognitive impairment. How hyperammonemia induces neuroinflammation remains unclear. We aimed to assess whether: chronic hyperammonemia induces peripheral inflammation, and whether this then contributes to neuroinflammation, altered neurotransmission and impaired spatial learning - before assessing whether this neuroinflammation and impairment is reversible following hyperammonemia elimination or treatment of peripheral inflammation with anti-TNF-α.
Chronic hyperammonemia was induced by feeding rats an ammonia-containing diet. Peripheral inflammation was analyzed by measuring PGE2, TNF-α, IL-6 and IL-10. We tested whether chronic anti-TNF-α treatment improves peripheral inflammation, neuroinflammation, membrane expression of glutamate receptors in the hippocampus and spatial learning.
Hyperammonemic rats show a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNF-α and IL-6, followed at around 10 days by reduced anti-inflammatory IL-10. Peripheral anti-TNF-α treatment prevents peripheral inflammation induction and the increase in IL-1b and TNF-α and microglia activation in hippocampus of the rats, which remain hyperammonemic. This is associated with prevention of the altered membrane expression of glutamate receptors and of the impairment of spatial memory assessed in the radial and Morris water mazes.
This report unveils a new mechanism by which chronic hyperammonemia induces neurological alterations: induction of peripheral inflammation. This suggests that reducing peripheral inflammation by safe procedures would improve cognitive function in patients with minimal hepatic encephalopathy.
This article unveils a new mechanism by which chronic hyperammonemia induces cognitive impairment in rats: chronic hyperammonemia per se induces peripheral inflammation, which mediates many of its effects on the brain, including induction of neuroinflammation, which alters neurotransmission, leading to cognitive impairment. It is also shown that reducing peripheral inflammation by treating rats with anti-TNF-α, which does not cross the blood-brain barrier, prevents hyperammonemia-induced neuroinflammation, alterations in neurotransmission and cognitive impairment.
慢性高血氨会引发神经炎症，从而导致认知障碍。高血氨引发神经炎症的机制尚不清楚。本研究旨在评估以下两种情况：慢性高血氨是否会引起外周炎症，以及这种炎症是否会导致神经炎症、神经递质传递改变和空间学习能力受损——然后再评估消除高血氨或用抗 TNF-α 治疗外周炎症后，这种神经炎症和损伤是否可逆。
通过给大鼠喂食含氨饮食来诱导慢性高血氨。通过测量 PGE2、TNF-α、IL-6 和 IL-10 来分析外周炎症。我们测试了慢性抗 TNF-α 治疗是否能改善外周炎症、神经炎症、海马体谷氨酸受体的膜表达和空间学习能力。
高氨血症大鼠表现出快速和可逆的外周炎症诱导，促炎因子 PGE2、TNF-α 和 IL-6 增加，大约 10 天后抗炎因子 IL-10 减少。外周给予抗 TNF-α 治疗可预防外周炎症的诱导以及大鼠海马体中 IL-1b 和 TNF-α 的增加和小胶质细胞的激活，尽管这些大鼠仍处于高血氨状态。这与谷氨酸受体膜表达的改变和空间记忆（在放射状和 Morris 水迷宫中评估）受损的预防有关。
本报告揭示了慢性高血氨诱导神经改变的新机制：诱导外周炎症。这表明，通过安全的方法减轻外周炎症可以改善轻度肝性脑病患者的认知功能。
本文揭示了慢性高血氨诱导大鼠认知障碍的新机制：慢性高血氨本身会引起外周炎症，这介导了其对大脑的许多影响，包括诱导神经炎症，改变神经递质传递，导致认知障碍。还表明，用不能穿过血脑屏障的抗 TNF-α 治疗大鼠，可预防高血氨诱导的神经炎症、神经递质传递改变和认知障碍。
