Modulation of GABAA receptors by neurosteroids. A new concept to improve cognitive and motor alterations in hepatic encephalopathy

Agustí, Ana; Llansola, Marta; Hernández‐Rabaza, Vicente; Cabrera‐Pastor, Andrea; Montoliú, Carmina; Felipo, Vicente

doi:10.1016/j.jsbmb.2015.08.020

Cited by 9 publications

(5 citation statements)

References 76 publications

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“…The precise mechanism that results in cognitive de cits following cholestatic liver disease is mainly unknown and therefore, there is no effective treatment available (Bashiri et al, 2018). There are some reports indicate that dysfunctions in several neurotransmitter systems, including acetylcholine, opioids,gamma-aminobutyric acid, noradrenaline, serotonin, dopamine, and glutamate may be involved in the pathogenesis of behavioral and cognitive abnormalities caused by cholestatic liver disease (Agusti et al, 2016;Hosseini et al, 2013;Nasehi et al, 2013a;Palomero-Gallagher et al, 2009). For example, it has been shown that the endogenous opioids increase in the cholestatic liver disease, supporting the involvement of the opioid system in its pathophysiology (Ebrahimkhani et al, 2006;Yurdaydin, 2001).…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Effects of GABAA Receptors in Dorsal Hippocampus on Memory Retention of Cholestatic Rats

Chen¹,

Zhang²,

Tayyebi

et al. 2021

Preprint

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The molecular mechanisms that result in cognitive deficits following cholestasis are mainly unknown. As there are many GABAA receptors in the hippocampus CA1 region and the crucial role for GABA in modulating memory, we evaluated the effects of GABAA receptor agents in the CA1 of cholestatic rats on memory retention. The interaction between GABAergic and opioidergic systems in the CA1 on memory was also investigated. The effects of administration of GABAA receptor agonist and antagonist, muscimol (60, 120 and 240 ng/ side) and bicuculline (100, 200 and 400 ng/ side), into CA1 on memory retention were studies using passive avoidance learning (PAL) task in bile duct ligated (BDL) rats. Naloxone (250 ng/ side), the mu-opioid receptor antagonist, was also co-administered alone or with bicuculline (400 ng/ side) to indicate the interaction between opioidergic and GABAergic system. Cholestasis inhibited memory retrieval is shown by the decrease in the step-through latency (STLr). Administration of muscimol or bicuculline alone after training potentiated or attenuated respectively amnesia in BDL rats dose-dependently. Naloxone (250 ng /side) alone increased STLr in BDL-treated rats. Bicuculline (100 ng/side) alone antagonized the amnesic effect of muscimol (120 ng/side). Co-administration of bicuculline and naloxone or muscimol and naloxone caused a significant difference in STLr compared to only naloxone treated rats which show the interaction between two systems on memory retention in cholestssis. Bicuculline (100 ng/side) microinjection alone antagonized the amnesic effect of muscimol (120 ng/side). We indicated the contribution of intra-CA1 GABAA receptors on memory retention in cholestatic rats by the PAL test. Blockade of each GABAA or mu-opioid receptors alone could attenuate the amnesia in BDL rats. Furthermore, blockade of both GABAA or mu-opioid receptors reversed the memory deficit in BDL-treated rats, which shows the interaction between GABAergic and opioidergic systems on memory retention in this test.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Effects of GABAA Receptors in Dorsal Hippocampus on Memory Retention of Cholestatic Rats

Chen¹,

Zhang²,

Tayyebi

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…1 Its pathophysiology is multifactorial and, while lowering of plasma ammonia levels reduces the risk and frequency of overt HE events, 2,3 recent studies suggest that the effects on the brain of hyperammonaemia and other injurious insults such as neuroinflammation are mediated by neurosteroid-induced allosteric activation of inhibitory GABA-A receptors. 1,4,5 The GABA-system, the brain's major inhibitory neurotransmitter system, regulates a variety of functions including learning, memory, vigilance and sleep. 6,7 GABA-A receptors are ionotropic heteropentameric assemblies with > − 20 distinct configurations, the functional characteristics of which vary depending on receptor subtype and cellular and subcellular localization.…”

Section: Introductionmentioning

confidence: 99%

A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy

Montagnese

Lauridsen

Vilstrup

et al. 2021

Journal of Hepatology

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Enters the CNS and reverses the inhibitory effects of neuroactive steroids on brain function in humans 9 Normalizes an elevated GABAergic tone, independent of ammonia 9 Improves cognitive function Cirrhosisis a growing problem and an end-stage disease Current drugs are targeting elevated ammonia levels Increased production of allopregnanolone Ammonia, inflammation Golexanolone: the only HE drug directly targeting CNS Golexanolone in HE CNS-related disorders Excessive GABAergic inhibition is a central driver of HE Excessive GABAergic tone Cirrhosis HighlightsHerein, we report findings from a pilot phase IIa study of golexanolone, a GABA-A receptor-modulating steroid antagonist, in clinical development for HE.Golexanolone was generally well tolerated and seemed to improve neuropsychiatric performance.These findings support a role for neurosteroids in the pathogenesis of HE-related sleepiness and vigilance.The results also suggest a role for golexanolone in the treatment of neurosteroid-mediated vigilance and cognitive disorders including HE.

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“…NeuN/Fox3 is a well‐recognized marker of postmitotic neurons and is involved in pathways related to neuronal circuit balance, neurogenesis, and dendritic spine density . GABRAB1 and GABRAG1 receptors are associated with older age and alcoholism in humans and animal models . Our results demonstrate the need for liver disease to be present to induce GABRAB1 and GABRAG1 and neuronal expression changes in the mouse brain regardless of gut microbiota composition and shed light on the multifaceted impact of these alterations.…”

Section: Discussionmentioning

confidence: 68%

“…(28) and GABRAG1 receptors are associated with older age and alcoholism in humans and animal models. (29)(30)(31) Our results demonstrate the need for liver disease to be present to induce GABRAB1 and GABRAG1 and neuronal expression changes in the mouse brain regardless of gut microbiota composition and shed light on the multifaceted impact of these alterations.…”

Section: Discussionmentioning

confidence: 69%

Neuroinflammation in Murine Cirrhosis Is Dependent on the Gut Microbiome and Is Attenuated by Fecal Transplant

et al. 2019

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Cirrhosis and hepatic encephalopathy (HE) is associated with an altered gut–liver–brain axis. Fecal microbial transplant (FMT) after antibiotics improves outcomes in HE, but the impact on brain function is unclear. The aim of this study is to determine the effect of colonization using human donors in germ‐free (GF) mice on the gut–liver–brain axis. GF and conventional mice were made cirrhotic using carbon tetrachloride and compared with controls in GF and conventional state. Additional GF mice were colonized with stool from controls (Ctrl‐Hum) and patients with cirrhosis (Cirr‐Hum). Stools from patients with HE cirrhosis after antibiotics were pooled (pre‐FMT). Stools from the same patients 15 days after FMT from a healthy donor were also pooled (post‐FMT). Sterile supernatants were created from pre‐FMT and post‐FMT samples. GF mice were colonized using stools/sterile supernatants. For all mice, frontal cortex, liver, and small/large intestines were collected. Cortical inflammation, synaptic plasticity and gamma‐aminobutyric acid (GABA) signaling, and liver inflammation and intestinal 16s ribosomal RNA microbiota sequencing were performed. Conventional cirrhotic mice had higher degrees of neuroinflammation, microglial/glial activation, GABA signaling, and intestinal dysbiosis compared with other groups. Cirr‐Hum mice had greater neuroinflammation, microglial/glial activation, and GABA signaling and lower synaptic plasticity compared with Ctrl‐Hum mice. This was associated with greater dysbiosis but no change in liver histology. Pre‐FMT material colonization was associated with neuroinflammation and microglial activation and dysbiosis, which was reduced significantly with post‐FMT samples. Sterile pre‐FMT and post‐FMT supernatants did not affect brain parameters. Liver inflammation was unaffected. Conclusion: Fecal microbial colonization from patients with cirrhosis results in higher degrees of neuroinflammation and activation of GABAergic and neuronal activation in mice regardless of cirrhosis compared with those from healthy humans. Reduction in neuroinflammation by using samples from post‐FMT patients to colonize GF mice shows a direct effect of fecal microbiota independent of active liver inflammation or injury.

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Modulation of GABAA receptors by neurosteroids. A new concept to improve cognitive and motor alterations in hepatic encephalopathy

Cited by 9 publications

References 76 publications

WITHDRAWN: Effects of GABAA Receptors in Dorsal Hippocampus on Memory Retention of Cholestatic Rats

WITHDRAWN: Effects of GABAA Receptors in Dorsal Hippocampus on Memory Retention of Cholestatic Rats

A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy

Neuroinflammation in Murine Cirrhosis Is Dependent on the Gut Microbiome and Is Attenuated by Fecal Transplant

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