Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain.
Fundacion Investigacion Hospital Clinico Valencia, INCLIVA, Valencia, Spain.
Acta Physiol (Oxf). 2019 Jun;226(2):e13270. doi: 10.1111/apha.13270. Epub 2019 Mar 22.
Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti-TNFα, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.
数以百万计的肝硬化患者患有轻微肝性脑病 (MHE)，存在轻度认知和协调障碍，降低了他们的生活质量和寿命。血氨升高和外周炎症协同作用诱导这些神经改变。我们提出，MHE 的出现是由于外周免疫系统的改变，这些改变传递到大脑，导致神经炎症改变神经传递，导致认知和运动改变。我们总结了表明肝硬化患者的 MHE 与免疫系统改变相关的研究，并且患有 HE 死亡的患者在小脑显示神经炎症，具有小胶质细胞和星形胶质细胞激活和浦肯野细胞丢失。我们还总结了 MHE 动物模型中关于外周炎症在神经炎症诱导中的作用、神经炎症如何改变神经传递以及这如何导致认知和运动改变的研究。这些研究确定了改善认知和运动功能的治疗靶点和治疗方法。MHE 大鼠在海马体中显示神经炎症和 NMDA 和 AMPA 受体膜表达改变，损害空间学习和记忆。小脑的神经炎症与 GABA 转运体和细胞外 GABA 的改变有关，这会损害 Y 迷宫中的运动协调和学习。这些改变可通过减少外周炎症（抗 TNFα、布洛芬）、神经炎症（萝卜硫素、p38 抑制剂）、GABA 能张力（印防己毒素、孕烯醇酮硫酸盐）或增加细胞外 cGMP（西地那非或 cGMP）的治疗来逆转。在与炎症、衰老和一些精神和神经退行性疾病相关的其他慢性疾病中也会发生已确定的机制。改善 MHE 的治疗方法也可能有益于治疗这些病理。
