The involvement of benzodiazepine receptor ligands in hepatic encephalopathy

Basile, Anthony S.; Jones, E. Anthony; Widler, Peter; Fisch, Hans-Ulrich; Schläepfer, Thomas E.; Reichen, Jürg; Schoch, Peter

doi:10.1002/hep.1840200241

Cited by 11 publications

(4 citation statements)

References 13 publications

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“…Agonists of GABA can act at the GABA receptor complex, and increased concentrations of the agonists are found in the brain in liver failure. 30 Neurosteroids produced in brain during acute liver failure led to increased GABAergic tone 31 and also, elevated intra-cerebral concentrations of GABA significantly decreased ornithine decarboxylase activity in the liver. 32 This was an index for decreased hepatic proliferation and function.…”

Section: Discussionmentioning

confidence: 99%

Increased Cortical Neuronal Survival During Liver Injury: Effect of Gamma Aminobutyric Acid and 5-HT Chitosan Nanoparticles

Joy¹,

Anju²,

Ajayan³

et al. 2014

Journal of Biomedical Nanotechnology

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Use of nanoparticulate drug delivery system for an effective therapeutic outcome against diseases gains immense hope in the study of drug delivery to partially hepatectomised rats. In the present study, partially hepatectomised rats treated with Gamma aminobutyric acid (GABA) and serotonin (5-HT) chitosan nanoparticles, individually and in combination, were evaluated to analyse their role in GABAB, and 5-HT2A receptors functional regulation, interrelated neuronal survival mechanisms by nuclear factor kappa B (NF-kappaB), tumour necrosis factor-a (TNF-alpha), Akt-1 and the antioxidant enzyme superoxide dismutase (SOD) in the cerebral cortex. A significant decrease in GABA, and 5-HT2A receptor numbers and gene expressions denoted a homeostatic adjustment by the cerebral cortex to trigger the sympathetic innervations during elevated DNA synthesis in the liver. GABAB, and 5-HT2A signalling directly influenced the cyclic AMP response element binding protein (CREB) expression, neuronal survival and ROS mediated cell damage which was confirmed from the gene expression of NF-kappaB, TNF-alpha, Akt-1 and SOD. In addition to enhanced hepatocyte proliferation, GABA and 5-HT chitosan nanoparticle treatment protected the neurons from ROS mediated cell damage and promoted their survival in the cerebral cortex. This has application in liver based diseases and treatments with nanosized active compounds.

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Section: Discussionmentioning

confidence: 99%

Increased Cortical Neuronal Survival During Liver Injury: Effect of Gamma Aminobutyric Acid and 5-HT Chitosan Nanoparticles

Joy¹,

Anju²,

Ajayan³

et al. 2014

Journal of Biomedical Nanotechnology

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“… Αυξθμζνθ ςυγκζντρωςθ νευροτοξικϊν ουςιϊν, όπωσ αμμωνία και μαγγάνιο 11 -113, 115, 116, 126, 136, 137  Διαταραχζσ τθσ μεταβίβαςθσ μζςω των ςυςτθμάτων γλουταμικοφ οξζοσ (αφξθςθ ςυγκζντρωςθσ εξωκυτταρικά) 102 -108, 123 -126, 135 ςεροτονίνθσ 135,140 κατεχολαμινϊν (κυρίωσ ντοπαμίνθσ και νορεπινεφρίνθσ) 138 -GABA (ενίςχυςθ τθσ αναςταλτικισ μεταβίβαςθσ) 120,131 οπιοειδϊν (αφξθςθ ενδογενϊν οπιοειδϊν) 118  Αφξθςθ του περιφερικοφ τφπου υποδοχζων των βενηοδιαηεπινϊν (ενιςχφουν τον οξειδωτικό μεταβολιςμό και τθν παραγωγι νευροςτεροειδϊν) 121,122,127,131,132  Αφξθςθ τθσ δράςθσ τθσ ςυνκετάςθσ του νιτρικοφ οξζοσ των νευρϊνων (οξειδωτικό stress, μεταβολζσ ςτθν εγκεφαλικι αιμάτωςθ) 112,141 Λδιαίτερο ενδιαφζρον παρουςιάηει θ πρόςφατα ανακαλυφκείςα οξινδόλθ. Ρρόκειται για μεταβολίτθ τθσ τρυπτοφάνθσ, με καταςταλτικζσ ιδιότθτεσ, που πιςτεφεται ότι ςυμμετζχει ςτθν αιτιοπακογζνεια τθσ θπατικισ εγκεφαλοπάκειασ.…”

Section: ρακοφυςιολογικοί μθχανιςμοίunclassified

“… θ μελζτθ των περιφερικϊν υποδοχζων των βενηοδιαηεπινϊν (benzodiazepine receptor ligands -BZRLs) ςτο πλάςμα χρόνιων θπατοπακϊν, χωρίσ ιδιαίτερα ενκαρρυντικά αποτελζςματα 121,122,127,129,130,132  ο προςδιοριςμόσ τθσ γουανυλικισ κυκλάςθσ (activation of soluble guanylate cyclase) ςτα λεμφοκφτταρα επίμυων. Χρθςιμεφει ωσ περιφερικόσ δείκτθσ διαταραχισ μεταβίβαςθσ μζςω του γλουταμικοφ -νιτρικοφ οξζοσ -cGMP των νευρϊνων (neuronal glutamatenitric oxide -cGMP).…”

Section: βιοχθμικοί δείκτεσ εγκεφαλικισ δυςλειτουργίασunclassified

“…Πλοι οι κατά καιροφσ μετροφμενοι δείκτεσ ςχετίηονται κυρίωσ με τουσ επιμζρουσ πακογενετικοφσ μθχανιςμοφσ πρόκλθςθσ θπατικισ εγκεφαλοπάκειασ. 112,119,121,122,127,129,130,132 Το ςφγχρονο ενδιαφζρον εντοπίηεται ςτθν ανεφρεςθ δεικτϊν που κα αντιπροςωπεφουν τθν εγκεφαλικι λειτουργία ςτο ςφνολό τθσ, ωσ ςυνιςταμζνθ των επιμζρουσ πακολογικϊν διαταραχϊν.…”

Section: εκσαγωγκκα στοκχεκαunclassified

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Μελέτη της αιμοδυναμικής του εγκεφάλου με τη βοήθεια της διακρανιακής doppler υπερηχογραφίας (transcranial doppler ultrasonography - TCD) σε ασθενείς με χρόνια ηπατική νόσο

Μόκα¹

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BackgroundCerebral haemodynamic and metabolic derangement is well known and common in patients withchronic liver disease or / and cirrhosis. It is often manifested as hepatic encephalopathy, although itscause and pathogenesis are not clearly understood and poorly elucidated. Patients with cirrhosisusually show alterations of cerebral perfusion and oxygenation, as well as changes of systemichaemodynamics and are thus prone to develop arterial hypotension, which might result in brainhypoperfusion, if cerebral autoregulation is impaired. Transcranial Doppler and Cerebral Oximetryare non invasive methods of neurological monitoring and are broadly used in the evaluation of theintracranial circulation and cerebral oxygenation status.Study Aims and ObjectivesThe aim of this open, comparative, non randomized, cross – sectional and longitudinal,observational clinical study was to evaluate brain haemodynamics in patients with chronic liverdisease and to test the degree of impairment of their cerebral autoregulatory mechanism, by usingTranscranial Doppler Ultrasonography. In addition, one of our basic scopes was to compare theseresults with those from Cerebral Oximetry and correlate them with the levels of blood S100bprotein.Material and MethodsOur study consisted of 40 healthy volunteers (Group I) and 40 patients with chronic liver disease(Group II). From those with chronic hepatic disease, 33 had liver cirrhosis (Group IIa) and 7 justchronic liver disease without cirrhosis (Group IIb). Regarding cerebral haemodynamics the baselineparametres that were examined included cerebral blood flow velocities, Vsyst, Vdias, Vmean,Pulsatility and Resistive Indices (PI &RI), as well as rSO2 values from Cerebral Oximetry. All thesevalues were recorded and studied bilaterally. The evaluation of the cerebral autoregulatorymechanism was performed with the continuous monitoring of mean arterial blood pressure, as wellas of the cerebral blood flow velocities, in the middle cerebral artery, bilaterally, during passivemovements of Trendelenbourg and Reverse Trendelenbourg, at 45ο, sequentially. The cerebralability of altering its perfusion and metabolism status was checked, again bilaterally, with themeasurement of the parametres mentioned above, after 1 min of active and passive movement ofthe right and left elbow and hand, with one movement happening after the other. All themeasurements mentioned above, were also evaluated in the subgroups of cirrhotic patients, with orwithout hepatic encephalopathy, with or without portal hypertension and according to the Child –Pugh stage of the disease. In all the subjects that were tested basic cardiorespiratory parametreswere recorded, at predetermined checking time – points. Finally, blood samples were withdrawnfrom both patients and healthy volunteers for investigation of basic haematological and biochemicalparametres, analysis of arterial blood gases and determination of the S100b protein blood levels.ResultsDuring the cross – sectional phase of our study, the cerebral blood flow velocities were found to belower in patients with chronic liver disease, when compared to healthy volunteers, without anysignificant differences between patients with or without cirrhosis. In addition, regarding TCDvelocities, important deviations were noticed in between cirrhotic patients of various stages, withthe detection of the lowest values in those of Child – Pugh Stage C. Furthermore, we foundstatistically significant differences, bilaterally, in between cirrhotic patients with or without hepaticencephalopathy, but without any strong correlation to its stage. PI and RI were significantly higher inpatients with cirrhosis than in controls and non – cirrhotic patients with chronic hepatic disease.Hepatic Encephalopathy patients were characterized by higher cerebral vascular resistance, compared to cirrhotic patients without any cerebral derangement. Similar results wereextrapolated from the Cerebral Oximetry measurements, with the lowest values of rSO2 beingdetected in patients of Child – Pugh Stage C and in those with hepatic encephalopathy also of Stage3. PI and RI were significantly correlated with the severity of cirrhosis and the existence of hepaticencephalopathy. In addition, they were significantly correlated with blood ammonia levels, PT andserum levels of albumin and bilirubin. Both Vmean and rSO2, as well as PI and RI were stronglycorrelated with S100b blood levels. In subjects with the highest values of S100b, the lowest values ofVmean and rSO2 were measured, whereas the highest PI and RI were calculated.During the longitudinal phase of our study, which refers to the autoregulatory mechanism testing,the following were noticed. Head down or head up provoked an increase or drop in blood pressurerespectively in all the subjects that were examined. Healthy controls and non cirrhotic patients had aprompt recovery of Vmean and a progressive recovery of arterial pressure, so that, after 120 sec,both parametres had returned to baseline. At 20 sec the recovery of flow velocity was faster thanthat of blood pressure. By contrast, patients with cirrhosis had a delayed and incomplete recovery ofboth parametres. The recovery of mean velocity paralleled that of arterial pressure, indicating animpaired cerebral autoregulation. Regarding passive and active movements of elbows and hands,we noticed an ipsilateral and contralateral increase of blood flow velocities and cerebral Oximetryvalues, but without any statistically significant differences between control subjects and chronichepatic patients, or their subgroups.ConclusionsThe results of this cross sectional and longitudinal study indicate that cerebral blood flow velocitiesand cerebral oximetry values are decreased in patients with chronic liver disease, whereas PI and RIare elevated, in strong correlation with the liver failure stage, the cirrhosis stage and the presence ofhepatic encephalopathy. This conclusion becomes more powerful when we take into account thestrong correlation of the measured indices and the levels of S100b protein. Cerebral autoregulationmechanism is often impaired in chronic hepatic patients, especially those with decompensatedcirrhosis. These patients can easily develop cerebral hypoperfusion, if arterial pressure falls abruptly.TCD Ultrasonography and Near Infrared Spectroscopy (Cerebral Oximetry) provide real time anduseful indices to assess and monitor cirrhotic patients and subjects with chronic liver failure.

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