Neurosteroids and Hepatic Encephalopathy: An Update on Possible Pathophysiologic Mechanisms

Author(s): Samir Ahboucha

Journal Name: Current Molecular Pharmacology

Volume 4 , Issue 1 , 2011

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Cerebral complications of liver failure either due to chronic or acute manifestations lead to a neurological disorder known as Hepatic encephalopathy (HE). Neurosteroids, synthesized in the brain mainly by astrocytes but also in other brain cells independently from peripheral steroidal sources such as adrenal and gonads, are suggested to play a role in the pathogenesis of HE. The mechanisms by which neurosteroids affect brain function are not totally elucidated but may involve both genomic and non genomic effects. On the one hand, neurosteroids bind and modulate different types of neuronal memebrane receptors. While neurosteroids may affect directly postsynaptic receptors including GABAA, 5-HT3, NMDA, glycine, and opioid receptors which have been involved in HE, neurosteroids effects through GABAA receptors may also compromise indirectly the function of neurons networking with GABAergic interneurons. On the other hand, some neurosteroids bind to intracellular receptors through which they also regulate gene expression, and there is substantial evidence confirming that expression of genes coding for key astrocytic and neuronal proteins is altered in HE. The mechanisms that trigger brain neurosteroid changes in HE are not yet established, but could involve (i) ammonia and manganese (in chronic HE)-induced translocator protein (TSPO) activation, (ii) neuroinflammation or (iii) blood-brain transfer of lipophylic neuroactive steroids. The present review summarizes evidence for the involvement of neurosteroids in HE and possible mechanisms for their altered brain production and central effects in human and experimental HE.

Keywords: Ammonia, cytokines, gene expression, hepatic encephalopathy, manganese, neurosteroids, neurotransmission, TSPO, GABAA receptors, HE, ALF, appetite, ODN, DBI, allopregnanolone, THDOC, DHEA, gonadectomy, adrenalectomy, immunohistochemistry, western blotting, in situ hybridization, cytochrome P450, enzymes, lipophilicity, BBB, cholesterol, mitochondria, PTBR, PBR, VDAC, ANC, heme, apoptosis, IMM, OMM, StAR, DHEAS, transcription, CNS, benzodiazepine, allosteric, flumazenil, sarmazenil, NMDA, NO, NMDA/NO/cGMP, BDL, hepatitis C, GFAP, GLUT-1, EAAT-2, GLYT-1, MAO-A, RT-PCR, TSPO mRNA, Endogenous, Brain, DBI1-86, hyperammonemia, MRI

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Article Details

Year: 2011
Page: [1 - 13]
Pages: 13
DOI: 10.2174/1874467211104010001

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