title: GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.
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.
authors.affiliation: Umecrine Cognition AB, Solna, Sweden; Umeå Neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Umeå, Sweden;
authors.forename: Maja
authors.initials: M
authors.lastname: Johansson
authors.affiliation: INCLIVA, Valencia, Spain; and.
authors.forename: Ana
authors.initials: A
authors.lastname: Agusti
authors.affiliation: Centro Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Llansola
authors.affiliation: INCLIVA, Valencia, Spain; and.
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.affiliation: Umeå Neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Umeå, Sweden;
authors.forename: Jessica
authors.initials: J
authors.lastname: Strömberg
authors.affiliation: Umeå Neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Umeå, Sweden;
authors.forename: Evgenya
authors.initials: E
authors.lastname: Malinina
authors.affiliation: Umeå Neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Umeå, Sweden;
authors.forename: Gianna
authors.initials: G
authors.lastname: Ragagnin
authors.affiliation: Umecrine Cognition AB, Solna, Sweden;
authors.forename: Magnus
authors.initials: M
authors.lastname: Doverskog
authors.affiliation: Umeå Neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Umeå, Sweden;
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Bäckström
authors.affiliation: Centro Investigación Príncipe Felipe, Valencia, Spain vfelipo@cipf.es.
authors.forename: Vicente
authors.identifier: http://orcid.org/0000-0003-3145-9538
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004336:Drug Antagonism; D057809:HEK293 Cells; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D006801:Humans; D006914:Hydroxysteroids / Q000494:pharmacology / Q000627:therapeutic use*; D022124:Hyperammonemia / Q000188:drug therapy*; D008124:Locomotion; D008297:Male; D018782:Maze Learning; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D006914:Hydroxysteroids; D011963:Receptors, GABA-A; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D011280:Pregnanolone
keywords: GABAA receptors; hepatic encephalopathy; hyperammonemia; neurosteroids