GABA-ergic tone hypothesis in hepatic encephalopathy – Revisited

Groiss, Stefan Jun; Butz, Markus; Baumgarten, Thomas J.; Füllenbach, Nur-Deniz; Häussinger, Dieter; Schnitzler, Alfons

doi:10.1016/j.clinph.2019.03.011

Cited by 11 publications

(5 citation statements)

References 43 publications

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“…HE patients showed a decreased cerebellar inhibition (in terms of increased GABA-mediated activity of Purkinje cells) that was related to disease severity, suggesting a dysfunction of the efferent cerebellar pathways (Hassan et al, 2019). A recent investigation supports this result showing a reduction of GABArgic inhibition, correlated with HE severity, although this was associated with an overall reduced cortico-spinal excitability (Groiss et al, 2019).…”

Section: Hepatic and Renal Diseasesmentioning

confidence: 82%

“…In this case, the predominant neurophysiological pattern is a hyperexcitability characterized by reduced GABAergic inhibition and facilitated glutamatergic transmission. However, hyperexcitability does not seem to be similarly associated with hyperammonemia-related damage in HE, where inconsistent results have been reported about changes in SICI, with reduced inhibition possibly characterizing only the severe stages ( Groiss et al, 2019 ). Finally, in other cognitive disorders associated with mechanisms involving specific molecular targets (such as the anti-NMDA receptor encephalitis), circuitry dysfunction appears more strictly related to these pathogenic factors, in which an altered LTP-like linked to NMDA receptor-dependent plasticity has been demonstrated ( Volz et al, 2016 ).…”

Section: Discussionmentioning

confidence: 93%

“…The TMS group included 4 studies on NPH (Zaaroor et al, 1997;Chistyakov et al, 2012;Nardone et al, 2019a;Agrawal et al, 2021), 11 on MS (Cucurachi et al, 2008;Mori et al, 2011Mori et al, , 2013Canham et al, 2015;Hofstadt-van Oy et al, 2015;Nantes et al, 2016;Chalah et al, 2018Chalah et al, , 2019Chaves et al, 2019Chaves et al, , 2021a, 6 on CD and other immune-mediated disorders (Pennisi et al, 2014;Bella et al, 2015;Pennisi et al, 2017;Tokimura et al, 2020;Fisicaro et al, 2021b;Lanza et al, 2021), 5 on endocrine disorders (Ozata et al, 1996;Rizzo et al, 2008;Terranova et al, 2016;Fried et al, 2017Fried et al, , 2019, 13 on liver and renal diseases (Meyer et al, 1991;Nolano et al, 1997;Córdoba et al, 2003;Battaglia et al, 2005;Cerri et al, 2010;McDonald et al, 2010;Dubbioso et al, 2016;Golaszewski et al, 2016;Nardone et al, 2016b;Groiss et al, 2019;Hassan et al, 2019;Stezin et al, 2019;Dubbioso et al, 2020), 9 on nutritional and alcohol-related disorders (Wu and Chu, 1996;Oishi and Mochizuki, 1999;…”

Section: Resultsmentioning

confidence: 99%

“…The TMS group included 4 studies on NPH ( Zaaroor et al, 1997 ; Chistyakov et al, 2012 ; Nardone et al, 2019a ; Agrawal et al, 2021 ), 11 on MS ( Cucurachi et al, 2008 ; Mori et al, 2011 , 2013 ; Canham et al, 2015 ; Hofstadt-van Oy et al, 2015 ; Nantes et al, 2016 ; Chalah et al, 2018 , 2019 ; Chaves et al, 2019 , 2021a , b ), 6 on CD and other immune-mediated disorders ( Pennisi et al, 2014 ; Bella et al, 2015 ; Pennisi et al, 2017 ; Tokimura et al, 2020 ; Fisicaro et al, 2021b ; Lanza et al, 2021 ), 5 on endocrine disorders ( Ozata et al, 1996 ; Rizzo et al, 2008 ; Terranova et al, 2016 ; Fried et al, 2017 , 2019 ), 13 on liver and renal diseases ( Meyer et al, 1991 ; Nolano et al, 1997 ; Córdoba et al, 2003 ; Battaglia et al, 2005 ; Cerri et al, 2010 ; McDonald et al, 2010 ; Dubbioso et al, 2016 ; Golaszewski et al, 2016 ; Nardone et al, 2016b ; Groiss et al, 2019 ; Hassan et al, 2019 ; Stezin et al, 2019 ; Dubbioso et al, 2020 ), 9 on nutritional and alcohol-related disorders ( Wu and Chu, 1996 ; Oishi and Mochizuki, 1999 ; Ravaglia et al, 2002 ; Misra et al, 2003 ; Atanassova et al, 2004 ; Di Lazzaro et al, 2004 ; Nardone et al, 2006 , 2010b , 2016a ), 7 on infectious or inflammatory diseases ( Misra and Kalita, 1998 ; Kalita and Misra, 2002 ; Lo and Ratnagopal, 2007 ; Volz et al, 2016 ; Nardone et al, 2019b ; Ortelli et al, 2021 ; Versace et al, 2021 ), 5 on sleep disorders (…”

Section: Resultsmentioning

confidence: 99%

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A comprehensive review of transcranial magnetic stimulation in secondary dementia

Lanza

Fisicaro

Dubbioso

et al. 2022

Front. Aging Neurosci.

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Although primary degenerative diseases are the main cause of dementia, a non-negligible proportion of patients is affected by a secondary and potentially treatable cognitive disorder. Therefore, diagnostic tools able to early identify and monitor them and to predict the response to treatment are needed. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological technique capable of evaluating in vivo and in “real time” the motor areas, the cortico-spinal tract, and the neurotransmission pathways in several neurological and neuropsychiatric disorders, including cognitive impairment and dementia. While consistent evidence has been accumulated for Alzheimer’s disease, other degenerative cognitive disorders, and vascular dementia, to date a comprehensive review of TMS studies available in other secondary dementias is lacking. These conditions include, among others, normal-pressure hydrocephalus, multiple sclerosis, celiac disease and other immunologically mediated diseases, as well as a number of inflammatory, infective, metabolic, toxic, nutritional, endocrine, sleep-related, and rare genetic disorders. Overall, we observed that, while in degenerative dementia neurophysiological alterations might mirror specific, and possibly primary, neuropathological changes (and hence be used as early biomarkers), this pathogenic link appears to be weaker for most secondary forms of dementia, in which neurotransmitter dysfunction is more likely related to a systemic or diffuse neural damage. In these cases, therefore, an effort toward the understanding of pathological mechanisms of cognitive impairment should be made, also by investigating the relationship between functional alterations of brain circuits and the specific mechanisms of neuronal damage triggered by the causative disease. Neurophysiologically, although no distinctive TMS pattern can be identified that might be used to predict the occurrence or progression of cognitive decline in a specific condition, some TMS-associated measures of cortical function and plasticity (such as the short-latency afferent inhibition, the short-interval intracortical inhibition, and the cortical silent period) might add useful information in most of secondary dementia, especially in combination with suggestive clinical features and other diagnostic tests. The possibility to detect dysfunctional cortical circuits, to monitor the disease course, to probe the response to treatment, and to design novel neuromodulatory interventions in secondary dementia still represents a gap in the literature that needs to be explored.

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Section: Hepatic and Renal Diseasesmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

A comprehensive review of transcranial magnetic stimulation in secondary dementia

Lanza

Fisicaro

Dubbioso

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…Hassan et al (2019) using TMS showed an enhanced GABAergic neurotransmission in cerebellum of cirrhotic patients with HE in vivo. Groiss et al (2019), also by TMS, showed a reduction of GABAergic neurotransmission of the motor cortex in vivo in patients with HE. This enhanced GABAergic neurotransmission plays a key role in the impairment of motor function and coordination, as discussed below.…”

Section: Gabaergic Neurotransmission Is Enhanced In Cerebellum In Hyp...mentioning

confidence: 81%

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

Llansola,

Arenas,

Sancho-Alonso

et al. 2024

Front. Pharmacol.

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Enhanced GABAergic neurotransmission contributes to impairment of motor coordination and gait and of cognitive function in different pathologies, including hyperammonemia and hepatic encephalopathy. Neuroinflammation is a main contributor to enhancement of GABAergic neurotransmission through increased activation of different pathways. For example, enhanced activation of the TNFα–TNFR1-NF-κB-glutaminase-GAT3 pathway and the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway in cerebellum of hyperammonemic rats enhances GABAergic neurotransmission. This is mediated by mechanisms affecting GABA synthesizing enzymes GAD67 and GAD65, total and extracellular GABA levels, membrane expression of GABAA receptor subunits, of GABA transporters GAT1 and GAT three and of chloride co-transporters. Reducing neuroinflammation reverses these changes, normalizes GABAergic neurotransmission and restores motor coordination. There is an interplay between GABAergic neurotransmission and neuroinflammation, which modulate each other and altogether modulate motor coordination and cognitive function. In this way, neuroinflammation may be also reduced by reducing GABAergic neurotransmission, which may also improve cognitive and motor function in pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission such as hyperammonemia, hepatic encephalopathy or Parkinson’s disease. This provides therapeutic targets that may be modulated to improve cognitive and motor function and other alterations such as fatigue in a wide range of pathologies. As a proof of concept it has been shown that antagonists of GABAA receptors such as bicuculline reduces neuroinflammation and improves cognitive and motor function impairment in rat models of hyperammonemia and hepatic encephalopathy. Antagonists of GABAA receptors are not ideal therapeutic tools because they can induce secondary effects. As a more effective treatment to reduce GABAergic neurotransmission new compounds modulating it by other mechanisms are being developed. Golexanolone reduces GABAergic neurotransmission by reducing the potentiation of GABAA receptor activation by neurosteroids such as allopregnanolone. Golexanolone reduces neuroinflammation and GABAergic neurotransmission in animal models of hyperammonemia, hepatic encephalopathy and cholestasis and this is associated with improvement of fatigue, cognitive impairment and motor incoordination. This type of compounds may be useful therapeutic tools to improve cognitive and motor function in different pathologies associated with neuroinflammation and increased GABAergic neurotransmission.

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Implication of Hypotension in the Pathogenesis of Cognitive Impairment and Brain Injury in Chronic Liver Disease

et al. 2023

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GABA-ergic tone hypothesis in hepatic encephalopathy – Revisited

Cited by 11 publications

References 43 publications

A comprehensive review of transcranial magnetic stimulation in secondary dementia

A comprehensive review of transcranial magnetic stimulation in secondary dementia

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

Implication of Hypotension in the Pathogenesis of Cognitive Impairment and Brain Injury in Chronic Liver Disease

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