Enhanced GABA release in cerebral cortical slices derived from rats with thioacetamide-induced hepatic encephalopathy

Wysmyk, Urszula; Oja, Simo S.; Saransaari, Pirjo; Albrecht, Jan

doi:10.1007/bf00968397

Cited by 30 publications

(6 citation statements)

References 13 publications

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“…Previous studies and our current data confirm that acute hepatic failure induced by TAA treatment can increase GABA [39] and glutamate levels [5] in the cerebral cortex. TAA induced an increase in both GABA (Figure S6A) and glutamate (Figure S6B) release compared with those of controls, causing a maximal 44% and 245% increase ( P <0.05), respectively.…”

Section: Resultssupporting

confidence: 89%

Abnormal Chloride Homeostasis in the Substancia Nigra Pars Reticulata Contributes to Locomotor Deficiency in a Model of Acute Liver Injury

Yang

Liu

et al. 2013

PLoS ONE

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BackgroundAltered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice.MethodsAlterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed.ResultsIn our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure.ConclusionOur data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure.

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Section: Resultssupporting

confidence: 89%

Abnormal Chloride Homeostasis in the Substancia Nigra Pars Reticulata Contributes to Locomotor Deficiency in a Model of Acute Liver Injury

Yang

Liu

et al. 2013

PLoS ONE

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“…Our data suggest that increased circulating (32, 33) and brain (33)(34)(35)(36) glutamine levels leading to increased concentrations and release of brain GABA may be involved in the hepatic encephalopathy of liver failure and ammonia toxicity (37). GABAergic transmission has been implicated in the pathogenesis of hepatic encephalopathy (38,39), and antagonists of GABA receptors can ameliorate manifestations of this disorder. Decreased glutamate levels have consistently been observed in brain homogenates from rats with acute liver failure (40) and from patients who died of hepatic coma (41).…”

Section: Discussionmentioning

confidence: 81%

“…GABAergic transmission has been implicated in the pathogenesis of hepatic encephalopathy (38,39), and antagonists of GABA receptors can ameliorate manifestations of this disorder. Decreased glutamate levels have consistently been observed in brain homogenates from rats with acute liver failure (40) and from patients who died of hepatic coma (41).…”

Section: Discussionmentioning

confidence: 99%

Oral L‐glutamine increases GABA levels in striatal tissue and extracellular fluid

Wang¹,

Maher²,

Wurtman³

2007

FASEB j.

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We explored the possibility that circulating glutamine affects gamma-aminobutyric acid (GABA) levels in rat striatal tissue and GABA concentrations in striatal extracellular fluid (ECF). Striatal microdialysates, each collected over a 20 min interval, were obtained after no treatment, oral L-glutamine (0.5 g/kg), or glutamine followed by NMDA (administered via the microdialysis probe). GABA concentrations were measured by HPLC using a stable OPA/sulfite precolumn derivatization and an electrochemical detection method. L-Glutamine administration significantly increased ECF GABA concentrations by 30%, and enhanced the response evoked by NMDA alone (70%) to 120% over baseline (all P<0.05). Striatal GABA levels increased significantly 2.5 h after oral L-glutamine (e.g., from 1.76 +/- 0.04 micromol/g in vehicle-treated rats to 2.00 +/- 0.15 micromol/g in those receiving 2.0 g/kg of glutamine). Striatal glutamine levels also increased significantly, but not those of glutamate. These data suggest that GABA synthesis in, and release from, rat striatum may be regulated in part by circulating glutamine. Hence, glutamine administration may provide a useful adjunct for treating disorders (e.g., anxiety, seizures) when enhanced GABAergic transmission is desired. Moreover, the elevation in plasma and brain glutamine associated with hepatic failure may, by increasing brain GABA release, produce some of the manifestations of hepatic encephalopathy.

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“…This rationale has been reproduced in various animal models of HE as well (Bassett et al, 1987;Gammal et al, 1990). Increased GABA'ergic tone in HE may be ascribed to increased levels of circulating natural benzodiazepines (Basile et al, 1991), increased synthesis of GABA A modulating neuroactive seroids (Ahboucha and Butterworth, 2007), increased availability of GABA and activation of GABA A receptors (Olasmaa et al, 1990;Wysmyk et al, 1992), while ammonia has also been found to increase GABA binding to the GABA A receptor (Ha and Basile, 1996). These events may also be attributed to an over zealous reaction to the potentially damaging levels of excitatory amino acids and elevated ammonia.…”

Section: The Neurochemistry Of Hepatic Encephalopathymentioning

confidence: 99%

Is major depressive disorder a metabolic encephalopathy?

Harvey

2008

Human Psychopharmacology

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Metabolic encephalopathy is an acute disturbance in cellular metabolism in the brain evoked by conditions of hypoxia, hypoglycaemia, oxidative stress and/or inflammation. It usually develops acutely or subacutely and is reversible if the systemic disorder is treated. If left untreated, however, metabolic encephalopathy may result in secondary structural damage to the brain. Most encephalopathies are present with neuropsychiatric symptoms, one in particular being depression. However, mood disorders are often co-morbid with cardiovascular, liver, kidney and endocrine disorders, while increasing evidence concurs that depression involves inflammatory and neurodegenerative processes. This would suggest that metabolic disturbances resembling encephalopathy may underscore the basic neuropathology of depression at a far deeper level than currently realized. Viewing depression as a form of encephalopathy, and exploiting knowledge gleaned from our understanding of the neurochemistry and treatment of metabolic encephalopathy, may assist in our understanding of the neurobiology of depression, but also in realizing new ideas in the pharmacotherapy of mood disorders.

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Enhanced GABA release in cerebral cortical slices derived from rats with thioacetamide-induced hepatic encephalopathy

Cited by 30 publications

References 13 publications

Abnormal Chloride Homeostasis in the Substancia Nigra Pars Reticulata Contributes to Locomotor Deficiency in a Model of Acute Liver Injury

Abnormal Chloride Homeostasis in the Substancia Nigra Pars Reticulata Contributes to Locomotor Deficiency in a Model of Acute Liver Injury

Oral L‐glutamine increases GABA levels in striatal tissue and extracellular fluid

Is major depressive disorder a metabolic encephalopathy?

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