GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.

Maja Johansson,Magnus Doverskog,Vicente Felipo,Carmina Montoliu,Ana Agusti,Evgenya Malinina,Jessica Strömberg,Torbjörn Bäckström,Gianna Ragagnin,Marta Llansola

doi:10.1152/ajpgi.00073.2015

Abstract

Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE.

Highlights

SEVERAL MILLION PATIENTS with liver cirrhosis suffer from minimal hepatic encephalopathy (MHE) with psychomotor slowing, attention deficits, mild cognitive impairment, and impaired visuomotor coordination [13, 22, 44]
We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and THDOC
There is no significant effect of GR3027 at either the ␣1␤2␥2L GABAA receptor [Ϫ3.1 Ϯ 1.7%, not significant (NS)] or the ␣5␤3␥2L GABAA receptor (Ϫ3.8 Ϯ 1.5%, NS) when GABA is the sole activator

Summary

Introduction

SEVERAL MILLION PATIENTS with liver cirrhosis suffer from minimal hepatic encephalopathy (MHE) with psychomotor slowing, attention deficits, mild cognitive impairment, and impaired visuomotor coordination [13, 22, 44]. These neurological alterations reduce the patient’s quality of life and ability to perform daily life tasks and increase the risk of traffic, work, and home accidents and the number of falls and hospitalizations. These treatments are not completely effective in reducing the neurological alterations, as they cannot eliminate hyperammonemia or inflammation continuously generated by the liver disease [14, 30, 35]. Overactivation of GABAA receptors by the agonists diazepam and muscimol or the neurosteroids allopregnanolone and 3␣,21-dihydroxy-5␣-pregnan-20-one (THDOC) impairs spatial learning and memory in the Morris water maze [19, 33, 34]

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