Golexanolone improves fatigue, motor incoordination and gait and memory in rats with bile duct ligation

Abstract

Background and AimsMany patients with the chronic cholestatic liver disease primary biliary cholangitis (PBC) show fatigue and cognitive impairment that reduces their quality of life. Likewise, rats with bile duct ligation (BDL) are a model of cholestatic liver disease. Current PBC treatments do not improve symptomatic alterations such as fatigue or cognitive impairment and new, more effective treatments are therefore required. Golexanolone reduces the potentiation of GABAA receptors activation by neurosteroids. Golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in rats with chronic hyperammonemia. The aims of the present study were to assess if golexanolone treatment improves fatigue and cognitive and motor function in cholestatic BDL rats and if this is associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum.MethodsRats were subjected to bile duct ligation. One week after surgery, oral golexanolone was administered daily to BDL and sham‐operated controls. Fatigue was analysed in the treadmill, motor coordination in the motorater, locomotor gait in the Catwalk, and short‐term memory in the Y‐maze. We also analysed peripheral inflammation, neuroinflammation, and GABAergic neurotransmission markers by immunohistochemistry and Western blot.ResultsBDL induces fatigue, impairs memory and motor coordination, and alters locomotor gait in cholestatic rats. Golexanolone improves these alterations, and this was associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum.ConclusionGolexanolone may have beneficial effects to treat fatigue, and motor and cognitive impairment in patients with the chronic cholestatic liver disease PBC.

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications

“…This was associated with reversal of the hyperammonemiaenhanced activation in cerebellum of the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways. Arenas et al (2023) extended these type of studies to rats with bile duct ligation (BDL), which are a model of both hepatic encephalopathy and of cholestatic liver disease. These rats show, in addition to cognitive and motor impairment other symptoms characteristic of cholestatic liver disease such as fatigue.…”

“…Current PBC treatments do not improve symptomatic alterations such as fatigue or cognitive impairment and new, more effective treatments are therefore required. Arenas et al (2023) assessed the effects of golexanolone on fatigue and cognitive and motor function in cholestatic BDL rats as well as on peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum. Golexanolone improves fatigue, memory impairment and motor incoordination and locomotor gait in BDL rats.…”

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“…in the rats with hyperammonemia and hepatic encephalopathy, and this is associated with reduced neuroinflammation and improvement of cognitive and motor function (Mincheva et al, 2022;Arenas et al, 2023). A similar reduction of glial activation is induced by bicuculline, an antagonist of GABA A receptors (Malaguarnera et al, 2019(Malaguarnera et al, , 2021, indicating that the reduction by golexanolone of glial activation is likely mediated by the reduction of activation of GABA A receptors.…”

“…The neurosteroids allopregnanolone and THDOC act as positive allosteric modulators of GABA A receptors. Golexanolone is a GABA A receptor-modulating steroid antagonist (GAMSA) (Johansson et al, 2016), which antagonizes the effects of allopregnanolone and THDOC on GABA A receptors (Bengtsson et al, 2023), thus reducing the potentiation of GABA A receptors in animal models and humans (Johansson et al, 2015(Johansson et al, , 2018Arenas et al, 2023).…”

“…Golexanolone reduces glial activation and neuroinflammation and improves cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. It is considered a promising therapeutic drug for ameliorating neurological impairments in patients with hepatic encephalopathy and primary biliary cholangitis (PBC) (Johansson et al, 2015;Montagnese et al, 2021;Mincheva et al, 2022;Arenas et al, 2023).…”