The Neurosteroid System: an Emerging Therapeutic Target for Hepatic Encephalopathy

Both acute and chronic liver failure induce cerebral complications known as hepatic encephalopathy (HE) and thought to selectively involve brain astrocytes. Alterations of astrocytic-neuronal cross talk occurs affecting brain function. In acute liver failure, astrocyte undergo swelling, which results in increased intracranial pressure and may lead to brain herniation. In chronic liver failure, Alzheimer-type II astrocytosis is a characteristic change. Neurosteroids (NS) synthesized in the brain mainly by astrocytes independent of peripheral steroidal sources (adrenals and gonads) are suggested to play a role in HE. NS bind and modulate different types of membrane receptors. Effects on the gamma amino butyric acid (GABA)-A receptor complex are the most extensively studied. For example, the NS tetrahydroprogesterone (allopregnanolone), and tetrahydrodeoxycorticosterone (THDOC) are potent positive allosteric modulators of GABA-A receptors. As a consequence of modulation of these receptors, NS are well-known to modulate inhibitory neurotransmission in the central nervous system. Some NS bind to intracellular receptors, and in this way may also regulate gene expression. In HE, it has been well documented that neurotransmission and gene expression alterations occur during the progression of the disease. This review summarizes findings of relevance for the involvement of NS in human and experimental HE.