Leone Paola, Mincheva Gergana, Balzano Tiziano, Malaguarnera Michele, Felipo Vicente, Llansola Marta
Mar Lab Department of Neuroscience, NYU Grossman School of Medicine Science Building, New York, NY 10016, USA.
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
Biomedicines. 2022 May 28;10(6):1263. doi: 10.3390/biomedicines10061263.
Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment.
非酒精性脂肪性肝病（NAFLD）患者可能会出现轻度认知障碍。海马体中的神经炎症介导了轻微肝性脑病（MHE）大鼠模型中的认知障碍。利福昔明治疗可逆转大部分患有MHE的肝硬化患者的认知障碍。然而，其潜在机制仍不清楚。这项工作的目的是评估作为NAFLD模型的轻度肝损伤大鼠是否存在海马体神经炎症和认知功能受损，利福昔明治疗是否能逆转这种情况，并研究其潜在机制。用四氯化碳诱导轻度肝损伤。评估免疫细胞浸润、神经胶质激活、细胞因子表达，以及海马体中的谷氨酸受体表达和认知功能。我们评估了利福昔明每日治疗对这些大鼠所表现出的改变的影响。轻度肝损伤大鼠表现出海马体神经炎症、谷氨酸N-甲基-D-天冬氨酸（NMDA）受体亚基的膜表达降低以及空间记忆受损。利福昔明可逆转C-C基序趋化因子配体2（CCL2）增加、单核细胞浸润、小胶质细胞激活以及肿瘤坏死因子α（TNFα）增加的情况，使NMDA受体表达正常化并改善空间记忆。因此，利福昔明可减轻轻度肝损伤大鼠的神经炎症并改善其认知功能，对于出现轻度认知障碍的NAFLD患者而言是一种有前景的治疗方法。
