Astroglial dysfunction in hepatic encephalopathy

While the pathogenesis of hepatic encephalopathy (HE) remains elusive, ther e is considerable evidence pointing to a key role of ammonia-induced dysfun ction of astrocytes in this condition. Deficits in the ability of astrocyte s to take up glutamate from the extracellular space may lead to abnormal gl utamatergic neurotransmission. Furthermore, excessive stimulation of neuron al and glial glutamate receptors by elevated extracellular levels of glutam ate 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. Thes e neurosteroids have potent positive modulatory effects on the neuronal GAB A(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 abnormalit ies as the edema appears to be principally caused by swelling of these cell s. Increased amounts of glutamine in astrocytes resulting from elevated bra in 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 gli opathy is a major factor in the pathogenesis of HE.