Astroglial dysfunction in hepatic encephalopathy.
While the pathogenesis of hepatic encephalopathy (HE) remains elusive, there is considerable evidence pointing to a key role of ammonia-induced dysfunction of astrocytes in this condition. Deficits in the ability of astrocytes to take up glutamate from the extracellular space may lead to abnormal glutamatergic neurotransmission. Furthermore, excessive stimulation of neuronal and glial glutamate receptors by elevated extracellular levels of glutamate may lead to excitotoxicity and greater glial dysfunction. Ammonia also causes upregulation of astroglial peripheral-type benzodiazepine receptors (PBRs) which is associated with increased production of neurosteroids. These neurosteroids have potent positive modulatory effects on the neuronal GABA(A) receptor which, combined with an ammonia-induced astroglial defect in GABA uptake, may result in enhanced GABAergic tone. Brain edema, associated with fulminant hepatic failure, may also result from astroglial abnormalities as the edema appears to be principally caused by swelling of these cells. Increased amounts of glutamine in astrocytes resulting from elevated brain ammonia levels may be a factor in this swelling. Other osmolytes such as glutathione may also be involved. Glial swelling may also result from NH4+ - and K+ -mediated membrane depolarization as well as by the actions of PBR agonists and neurosteroids. These findings show that an ammonia-induced gliopathy is a major factor in the pathogenesis of HE.
Norenberg
M D
MD
Department of Pathology, University of Miami School of Medicine, FL 33101, USA. mnorenbe@mednet.med.miami.edu
D000641:Ammonia / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D018079:Receptors, GABA / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology
D018079:Receptors, GABA; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D000641:Ammonia