Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Umecrine Cognition AB, Solna, Sweden.
Liver Int. 2024 Feb;44(2):433-445. doi: 10.1111/liv.15782. Epub 2023 Nov 27.
Many 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 GABA 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.
Rats 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.
BDL 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.
Golexanolone may have beneficial effects to treat fatigue, and motor and cognitive impairment in patients with the chronic cholestatic liver disease PBC.
许多患有原发性胆汁性胆管炎（PBC）这种慢性胆汁淤积性肝病的患者会出现疲劳和认知障碍，从而降低其生活质量。同样，胆管结扎（BDL）的大鼠是胆汁淤积性肝病的模型。目前的 PBC 治疗方法并不能改善疲劳或认知障碍等症状改变，因此需要新的、更有效的治疗方法。Golexanolone 可降低神经甾体对 GABA 受体激活的增效作用。Golexanolone 可减轻外周炎症和神经炎症，并改善慢性高氨血症大鼠的认知和运动功能。本研究的目的是评估 golexanolone 治疗是否能改善胆汁淤积性 BDL 大鼠的疲劳、认知和运动功能，以及是否与小脑外周炎症、神经炎症和 GABA 能神经传递的改善有关。
大鼠接受胆管结扎。手术后 1 周，对 BDL 和假手术对照组大鼠进行每日口服 golexanolone 治疗。在跑步机上分析疲劳，在运动自动机上分析运动协调，在 Catwalk 上分析运动步态，在 Y 迷宫上分析短期记忆。我们还通过免疫组织化学和 Western blot 分析外周炎症、神经炎症和 GABA 能神经传递标志物。
BDL 可引起胆汁淤积大鼠的疲劳、记忆和运动协调受损，并改变其运动步态。Golexanolone 可改善这些改变，与小脑外周炎症、神经炎症和 GABA 能神经传递的改善有关。
Golexanolone 可能对治疗慢性胆汁淤积性肝病 PBC 患者的疲劳、运动和认知障碍具有有益作用。
