Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy

Cauli, Omar; Rodrigo, Regina; Llansola, Marta; Montoliú, Carmina; Monfort, Pilar; Piedrafita, Blanca; Mlili, Nisrin El; Boix, Jordi; Agustí, Ana; Felipo, Vicente

doi:10.1007/s11011-008-9115-4

Cited by 131 publications

(103 citation statements)

References 47 publications

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“…6A). Acute liver failure may be associated with neuronal death due to glutamate-induced excitotoxicity (16,24), the effect that, based on our study, may be blocked by FIN.…”

Section: Discussionsupporting

confidence: 53%

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Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Mladenović

Hrnčić

Petronijević

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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(HE). This study evaluated the effects of finasteride, inhibitor of neurosteroid synthesis, on motor, EEG, and cellular changes in rat brain in thioacetamide-induced HE. Male Wistar rats were divided into the following groups: 1) control; 2) thioacetamide-treated group, TAA (300 mg·kg Ϫ1 ·day Ϫ1 ); 3) finasteride-treated group, FIN (50 mg·kg Ϫ1 ·day Ϫ1 ); and 4) group treated with FIN and TAA (FIN ϩ TAA). Daily doses of TAA and FIN were administered in three subsequent days intraperitoneally, and in the FIN ϩ TAA group FIN was administered 2 h before every dose of TAA. Motor and reflex activity was determined at 0, 2, 4, 6, and 24 h, whereas EEG activity was registered about 24 h after treatment. The expressions of neuronal (NeuN), astrocytic [glial fibrilary acidic protein (GFAP)], microglial (Iba1), and oligodendrocyte (myelin oligodendrocyte glycoprotein) marker were determined 24 h after treatment. While TAA decreased all tests, FIN pretreatment (FIN ϩ TAA) significantly improved equilibrium, placement test, auditory startle, head shake reflex, motor activity, and exploratory behavior vs. the TAA group. Vital reflexes (withdrawal, grasping, righting and corneal reflex) together with mean EEG voltage were significantly higher (P Ͻ 0.01) in the FIN ϩ TAA vs. the TAA group. Hippocampal NeuN expression was significantly lower in TAA vs. control (P Ͻ 0.05). Cortical Iba1 expression was significantly higher in experimental groups vs. control (P Ͻ 0.05), whereas hippocampal GFAP expression was increased in TAA and decreased in the FIN ϩ TAA group vs. control (P Ͻ 0.05). Finasteride improves motor and EEG changes in TAA-induced HE and completely prevents the development of hepatic coma. motor tests; electroencephalography; cellular markers HEPATIC ENCEPHALOPATHY (HE) represents a clinical syndrome characterized by neurological and psychiatric disturbances that develop as a result of acute or chronic liver failure (21). Various mechanisms are involved in the pathogenesis of HE, including changes in neurotransmission (17), oxidative stress, bioenergetic failure, mitochondrial permeability transition (49), inflammatory response, and immune dysfunction (14, 52), due to accumulation of various toxins in the organism, principally ammonia (4).Changes in glutamatergic and GABAergic transmission have an important role in the development of HE (13, 16). Both acute and chronic liver failure were found to be associated with increased GABAergic activity due to increased neurosteroid synthesis. Neurosteroids are steroid compounds, synthesized in mitochondria of glial cells and neurons from cholestrol (2). Cholesterol is taken up into mitochondria via the activation of translocator protein (TSPO), a multimeric complex that spans both outer and inner mitochondrial membrane. Ammonia and manganese, toxins accumulated in HE, and proinflammatory cytokines upregulate components of TSPO and increase cholesterol uptake into the mitochondrion (2, 4). Cholesterol serves as a substrate for increased synthesis of neurosteroids, including all...

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“…6A). Acute liver failure may be associated with neuronal death due to glutamate-induced excitotoxicity (16,24), the effect that, based on our study, may be blocked by FIN.…”

Section: Discussionsupporting

confidence: 53%

“…Changes in glutamatergic and GABAergic transmission have an important role in the development of HE (13,16). Both acute and chronic liver failure were found to be associated with increased GABAergic activity due to increased neurosteroid synthesis.…”

mentioning

confidence: 99%

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Mladenović

Hrnčić

Petronijević

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Interestingly, prolonged cortical neuron survival has been reported to occur in hyperammonemic animals given the NMDA receptor antagonists MK-801 and 2-amino-5-phosphonovaleric acid (APV) [29]. The glutamatergic stimuli secondary to prolonged brain exposure to ammonia can also affect activation of other neurotransmission systems, such as gamma-aminobutyric acidd (GABA) or benzodiazepine receptors [30] …”

Section: Glutamatergic Systemmentioning

confidence: 99%

Hyperammonemia in review: pathophysiology, diagnosis, and treatment

2011

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Ammonia is an important source of nitrogen and is required for amino acid synthesis. It is also necessary for normal acid-base balance. When present in high concentrations, ammonia is toxic. Endogenous ammonia intoxication can occur when there is impaired capacity of the body to excrete nitrogenous waste, as seen with congenital enzymatic deficiencies. A variety of environmental causes and medications may also lead to ammonia toxicity. Hyperammonemia refers to a clinical condition associated with elevated ammonia levels manifested by a variety of symptoms and signs, including significant central nervous system (CNS) abnormalities. Appropriate and timely management requires a solid understanding of the fundamental pathophysiology, differential diagnosis, and treatment approaches available. The following review discusses the etiology, pathogenesis, differential diagnosis, and treatment of hyperammonemia.

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“…Chronic hyperammonemia per se induces neuroinflammation that contributes to the neurological alterations in MHE [5]. The mechanisms responsible for some specific neurological alterations in MHE are beginning to be clarified in animal models [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Sildenafil Reduces Neuroinflammation and Restores Spatial Learning in Rats with Hepatic Encephalopathy. Underlying Mechanisms

Hernández‐Rabaza¹,

Agustí²,

Cabrera‐Pastor³

et al. 2016

Journal of Hepatology

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Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy

Cited by 131 publications

References 47 publications

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Hyperammonemia in review: pathophysiology, diagnosis, and treatment

Sildenafil Reduces Neuroinflammation and Restores Spatial Learning in Rats with Hepatic Encephalopathy. Underlying Mechanisms

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