Loic Le Guennec, Sarah Mouri, Dominique Thabut, Nicolas Weiss
{"title":"肝性脑病的血脑屏障功能障碍:病理生理学、诊断评估和治疗观点。","authors":"Loic Le Guennec, Sarah Mouri, Dominique Thabut, Nicolas Weiss","doi":"10.1007/s11011-025-01645-3","DOIUrl":null,"url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) is defined as the spectrum of neurological and neuro-psychological disturbances that complicate liver insufficiency and/or portosystemic shunt and is associated with excess mortality, impaired quality of life and a higher risk of traffic accidents. In addition to hyperammonaemia, systemic inflammation is now recognised as a pivotal precipitant of HE. Accumulating evidence over the past three decades indicates that dysfunction of the blood-brain barrier (BBB)-the multicellular interface that regulates molecular, immune and haemodynamic exchanges between brain and blood-also plays a central pathogenic role. In experimental and clinical HE, cytokine- and ammonia-driven loss of tight-junction proteins (claudin-5, occludin, ZO-1/-2), astrocytic aquaporin-4 mislocalisation, pericyte structural injury and impaired glymphatic flow converge to increase vascular permeability and promote cytotoxic and vasogenic oedema. Concurrent activation of microglia and up-regulation of endothelial adhesion molecules facilitate leukocyte recruitment, whereas NF-κB-dependent re-programming of ATP-binding cassette and solute-carrier transporters alters cerebral handling of xenobiotics, bile acids and amino acids. A better understanding of these interconnected mechanisms opens the way to BBB-directed interventions such as Angiopoietin-1 analogues, sphingosine-1-phosphate-receptor modulators or claudin-5 peptidomimetics that could complement classic ammonia-lowering therapies. This review critically examines how BBB dysfunction contributes to the pathogenesis of HE and summarizes emerging therapeutic approaches targeting the barrier.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"223"},"PeriodicalIF":3.5000,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Blood-brain barrier dysfunction in hepatic encephalopathy: pathophysiology, diagnostic assessment and therapeutic perspectives.\",\"authors\":\"Loic Le Guennec, Sarah Mouri, Dominique Thabut, Nicolas Weiss\",\"doi\":\"10.1007/s11011-025-01645-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hepatic encephalopathy (HE) is defined as the spectrum of neurological and neuro-psychological disturbances that complicate liver insufficiency and/or portosystemic shunt and is associated with excess mortality, impaired quality of life and a higher risk of traffic accidents. In addition to hyperammonaemia, systemic inflammation is now recognised as a pivotal precipitant of HE. Accumulating evidence over the past three decades indicates that dysfunction of the blood-brain barrier (BBB)-the multicellular interface that regulates molecular, immune and haemodynamic exchanges between brain and blood-also plays a central pathogenic role. In experimental and clinical HE, cytokine- and ammonia-driven loss of tight-junction proteins (claudin-5, occludin, ZO-1/-2), astrocytic aquaporin-4 mislocalisation, pericyte structural injury and impaired glymphatic flow converge to increase vascular permeability and promote cytotoxic and vasogenic oedema. Concurrent activation of microglia and up-regulation of endothelial adhesion molecules facilitate leukocyte recruitment, whereas NF-κB-dependent re-programming of ATP-binding cassette and solute-carrier transporters alters cerebral handling of xenobiotics, bile acids and amino acids. A better understanding of these interconnected mechanisms opens the way to BBB-directed interventions such as Angiopoietin-1 analogues, sphingosine-1-phosphate-receptor modulators or claudin-5 peptidomimetics that could complement classic ammonia-lowering therapies. This review critically examines how BBB dysfunction contributes to the pathogenesis of HE and summarizes emerging therapeutic approaches targeting the barrier.</p>\",\"PeriodicalId\":18685,\"journal\":{\"name\":\"Metabolic brain disease\",\"volume\":\"40 5\",\"pages\":\"223\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-06-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Metabolic brain disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s11011-025-01645-3\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Metabolic brain disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11011-025-01645-3","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Blood-brain barrier dysfunction in hepatic encephalopathy: pathophysiology, diagnostic assessment and therapeutic perspectives.
Hepatic encephalopathy (HE) is defined as the spectrum of neurological and neuro-psychological disturbances that complicate liver insufficiency and/or portosystemic shunt and is associated with excess mortality, impaired quality of life and a higher risk of traffic accidents. In addition to hyperammonaemia, systemic inflammation is now recognised as a pivotal precipitant of HE. Accumulating evidence over the past three decades indicates that dysfunction of the blood-brain barrier (BBB)-the multicellular interface that regulates molecular, immune and haemodynamic exchanges between brain and blood-also plays a central pathogenic role. In experimental and clinical HE, cytokine- and ammonia-driven loss of tight-junction proteins (claudin-5, occludin, ZO-1/-2), astrocytic aquaporin-4 mislocalisation, pericyte structural injury and impaired glymphatic flow converge to increase vascular permeability and promote cytotoxic and vasogenic oedema. Concurrent activation of microglia and up-regulation of endothelial adhesion molecules facilitate leukocyte recruitment, whereas NF-κB-dependent re-programming of ATP-binding cassette and solute-carrier transporters alters cerebral handling of xenobiotics, bile acids and amino acids. A better understanding of these interconnected mechanisms opens the way to BBB-directed interventions such as Angiopoietin-1 analogues, sphingosine-1-phosphate-receptor modulators or claudin-5 peptidomimetics that could complement classic ammonia-lowering therapies. This review critically examines how BBB dysfunction contributes to the pathogenesis of HE and summarizes emerging therapeutic approaches targeting the barrier.
期刊介绍:
Metabolic Brain Disease serves as a forum for the publication of outstanding basic and clinical papers on all metabolic brain disease, including both human and animal studies. The journal publishes papers on the fundamental pathogenesis of these disorders and on related experimental and clinical techniques and methodologies. Metabolic Brain Disease is directed to physicians, neuroscientists, internists, psychiatrists, neurologists, pathologists, and others involved in the research and treatment of a broad range of metabolic brain disorders.