Experimental Hepatic Encephalopathy Research Articles

Use of bee venom in preventive medicine: An experimental hepatic encephalopathy study in rats.

Bee venom is used for medicinal purposes, including the treatment of neurological and liver diseases, but its use as a primary health care approach for preventive purposes requires further exploration. The aim of this study was to provide the first investigation into the possible protective effects of bee venom against hepatic encephalopathy, a serious neurodegenerative disease. An experimental animal study was conducted in which healthy albino Sprague-Dawley rats were randomized into three groups: healthy, control and bee venom groups. All rats were tested for locomotor activity at the beginning and end of the study. No intervention was made in the healthy group, whereas hepatic encephalopathy was induced in the control and bee venom groups by the administration of thioacetamide (TAA) (200mg/kg/day). The bee venom group also received bee venom (5mg/kg/day) subcutaneously every day for 14 days prior to the TAA administration. The results for the final locomotor activity tests were statistically better in the bee venom group than in the control group, supporting a beneficial effect of prophylactic bee venom application. Blood ammonia levels and liver weights, determined as indicators of inflammation, were lower in the bee venom group than in the control group and were close to levels in the healthy group, but not statistically significant. Bee venom administration has protective effects against the development of hepatic encephalopathy and offers a promising therapeutic opportunity in preventive medicine.

Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes

Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the most important ammonia-metabolizing cells in the brain, and microglia, the main immunomodulatory cells in the brain, have been heavily implicated in HE development. As insight into cellular perturbations driving brain pathology remains largely elusive, we aimed to investigate cell-type specific transcriptomic changes in the HE brain. In the recently established mouse bile duct ligation (BDL) model of HE, we performed RNA-Seq of sorted astrocytes and microglia at 14 and 28 days after induction. This revealed a marked transcriptional response in both cell types which was most pronounced in microglia. In both cell types, pathways related to inflammation and hypoxia, mechanisms commonly implicated in HE, were enriched. Additionally, astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction. Accordingly, both monocytes and neutrophils accumulated in the BDL mouse brain. Time-dependent changes were limited in both cell types, suggesting early establishment of a pathological phenotype. While HE is often considered a unique form of encephalopathy, astrocytic and microglial transcriptomes showed significant overlap with previously established gene expression signatures in other neuroinflammatory diseases like septic encephalopathy and stroke, suggesting common pathophysiological mechanisms. Our dataset identifies key molecular mechanisms involved in preclinical HE and provides a valuable resource for development of novel glial-directed therapeutic strategies.Graphical

Development of an experimental hepatic encephalopathy in a rabbit model: Biochemical and immunohistochemical study

This study was designed to estimate the biochemical, histochemical, and immunohistochemical aspects of hepatic encephalopathy (HE) induced experimentally by using Thioacetamide (TAA). Twenty-four male rabbits were separated into four main groups (6 each), the Control group (group I) and Group II; rabbits were injected with TAA dissolved in distal water at 200 mg/kg B.W. twice weekly for eight weeks. Group III was given silymarin orally dissolved in saline 200mg/kg B.W. daily for eight weeks. Group IV animals received TAA and Silymarin 200 mg/kg B.W. for eight weeks. The results revealed animals treated with TAA indicated a significant decrease in the level of TSP and a significant increase in the levels of TSB, ALP, ALT, and AST. Histopathological examination of each liver and brain indicates necrosis of the hepatocytes, Cholangitis, biliary duct epithelium hyperplasia and preductular fibrosis, and collagen fiber deposition in the portal triad. Necrosis of the neurons, Purkinjean, and molecular cells with a decrease in granular cells and thickening of meninges. The histochemical examination of the liver revealed the presence of fibrosis in the portal area and the peri-lobular septa and the presence portal to portal bridging fibrosis. The immunohistochemical stain of the liver section revealed a positive reaction for collagen type IV, especially in/and around the portal tried as well as in the septa between the lobules. In conclusion, in the rabbit's model, hepatotoxicity to the early stages of the pathogenesis of hepatoencephalopathy.

Molecular mechanisms involved in the effects of morin in experimental hepatic encephalopathy.

This study aimed to investigate the possible usefulness of morin flavonoid in comparison to silymarin as a hepatic/neuronal-supportive agent with similar effects and higher bioavailability in a rat model of hepatic encephalopathy (HE). Morin effects on rat liver and brain were evaluated post-induction of HE by thioacetamide (TAA; 200 mg/kg/day for 3 successive days). Then, the serum activities of aspartate transaminase (AST) and alanine transaminase (ALT) together with ammonia concentration were estimated to assess the liver function. Also, the degree of brain effects was evaluated via the assessment of brain contents of reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin (IL-1β) together with glutathione peroxidase (GPx) activity. In addition, the apoptotic and inflammatory changes in brain and liver tissues were also assessed via immunohistochemical examination. Our findings revealed a promising effect of morin against HE complications; as it corrected the liver functions, attenuated the brain/liver tissue injuries, and reduced the apoptotic and inflammatory insults of HE on both organs. These effects are comparable to those of silymarin. Morin could be introduced as a promising hepato- and neuro-therapeutic adjuvant in HE-associated neuronal complications especially in cases like silymarin intolerance.

Glutamine synthetase expression in the brain during experimental acute liver failure (immunohistochemical study)

The aim of the study was to determine the immunohistochemical level of glutamine synthetase (GS) expression in different brain regions in the conditions of experimental acute liver failure in rats.
 Materials and methods. The study was conducted in Wistar rats: 5 sham (control) animals and 10 rats with acetaminophen induced liver failure model (AILF). The immunohistochemical study of GS expression in the sensorimotor cortex, white matter, hippocampus, thalamus, caudate nucleus/putamen was carried out in the period of 12-24 h after acetaminophen treatment.
 Results. Beginning from the 6th hour after acetaminophen treatment all AILF-animals showed the progressive increase in clinical signs of acute brain disfunction finished in 6 rats by comatose state up to 24 h - they constituted subgroup AILF-B, “non-survived”. 4 animals survived until the 24 h - subgroup AILF-A, “survived”. In the AILF-B group, starting from 16 to 24 hours after treatment, a significant (relative to control) regionally-specific dynamic increase in the level of GS expression was observed in the brain: in the cortex – by 307.33 %, in the thalamus – by 249.47%, in the hippocampus – by 245.53%, in the subcortical white matter – by 126.08%, from 12th hour – in the caudate nucleus/putamen, by 191.66 %; with the most substantive elevation of GS expression in the cortex: by 4.07 times.
 Conclusion. Starting from the 16th hours after the acetaminophen treatment (from the 12th h in the caudate nucleus/putamen region) and up to 24 h, it is observed reliable compared to control dynamic increase in GS protein expression in the cortex, white matter, hippocampus, thalamus, caudate nucleus/putamen of the rat brain with the most significant elevation in the cortex among other regions. The heterogeneity in the degree of GS expression rising in different brain regions potentially may indicate regions more permeable for ammonia and/or other systemic toxic factors as well as heterogeneous sensitivity of brain regions to deleterious agents in conditions of AILF. Subsequently, revealed diversity in the GS expression reflects the specificity of reactive response of local astroglia in the condition of AILF-encephalopathy during specific time-period. The dynamic increase in the GS expression associated with impairment of animal state, indicates involvement of increased GS levels in the mechanisms of experimental acute hepatic encephalopathy.

Reduced TH expression and α-synuclein accumulation contribute towards nigrostriatal dysfunction in experimental hepatic encephalopathy.

The present work examines α-synuclein expression in the nigrostriatal system of a rat chronic hepatic encephalopathy model induced by portacaval anastomosis (PCA). There is evidence that dopaminergic dysfunction in disease conditions is strongly associated with such expression. Possible relationships among dopaminergic neurons, astroglial cells and α-synuclein expression were sought. Brain tissue samples from rats at 1 and 6 months post-PCA, and controls, were analysed immunohistochemically using antibodies against tyrosine hydroxylase (TH), α-synuclein, glial fibrillary acidic protein (GFAP) and ubiquitin (Ub). In the control rats, TH immunoreactivity was detected in the neuronal cell bodies and processes in the substantia nigra pars compacta (SNc). A dense TH-positive network of neurons was also seen in the striatum. In the PCA-exposed rats, however, a reduction in TH-positive neurons was seen at both 1 and 6 months in the SNc, as well as a reduction in TH-positive fibres in the striatum. This was coincident with the appearance of α-synuclein-immunoreactive neurons in the SNc; some of the TH-positive neurons also showed α-synuclein immunoreactivity. In addition, α-synuclein accumulation was seen in the SNc and striatum at both 1 and 6 months post-PCA, whereas α-synuclein was only mildly expressed in the nigrostriatal pathway of the controls. Astrogliosis was also seen following PCA, as revealed by increased GFAP expression from 1 month to 6 months post-PCA in both the SN and striatum. The astroglial activation level in the SN paralleled the reduced neuronal expression of TH throughout PCA exposure. α-synuclein accumulation following PCA may induce dopaminergic dysfunction via the downregulation of TH, as well as astroglial activation.

The healing effect of Curcuma longa on liver in experimental acute hepatic encephalopathy of rat

Hepatic encephalopathy (HE) is a potentially reversible spectral neuropsychiatric state that complicates liver disease and negatively affects the prognosis. This study evaluated the effect of Curcuma longa in acute HE in rat and determined the behavioral, biochemical, and histological changes. Forty male Sprague Dawley rats were randomly divided into the control and three experimental groups. Thioacetamide (TAA, 300 mg/kg) was administered intraperitoneally to induce acute HE. Curcumin was administered orally at doses of 200, 300, and 400 mg/kg. The animals’ behavior, levels of ammonia, alkaline phosohatase (ALP), alanine transaminase (ALT), and aspartate transaminase (AST) enzymes were evaluated. The livers were evaluated histologically too. TAA could successfully induce inflammation and necrosis in hepatic tissue. Regarding the behavioral score, an increase in the dose of curcumin was correlated with a significant decrease in behavioral score. Ammonia, ALP, ALT, and AST levels were significantly lower among curcumin-receiving groups when compared with the control group, which was dose dependent. Histologically, curcumin was shown to reduce inflammation and necrosis in hepatic tissue, which was dose dependent too. Our findings revealed that curcumin could successfully prevent acute HE, which may happen due to a reduction in release of free radicals in the liver.

Upregulation of α-synuclein expression in the rat cerebellum in experimental hepatic encephalopathy

The overexpression of alpha-synuclein has been associated with neurodegenerative diseases, especially when the protein aggregates to form insoluble structures. The present study examined the effect of chronic hyperammonaemia on alpha-synuclein expression in the rat cerebellum following portacaval anastomosis (PCA). Immunohistochemical and western blot determinations were performed 1 month and 6 months after the PCA procedure. A time-dependent increase in alpha-synuclein expression was seen in the cerebellar grey matter compared with the controls. At 1 month post PCA, alpha-synuclein-immunopositive material was observed in the molecular layer, while the Purkinje cells showed weak alpha-synuclein expression, and alpha-synuclein aggregates were observed throughout the granular layer. At 6 months post PCA, alpha-synuclein expression was significantly increased compared with the controls. alpha-synuclein-immunostained astroglial cells were also found; the Bergmann glial cells showed alpha-synuclein-positive processes in the molecular layer of PCA-exposed rats, and in the granular layer, perivascular astrocytes showed intense alpha-synuclein immunoreactivity, as indicated by colocalization of alpha-synuclein with glial fibrillary acidic protein (GFAP). In addition, ubiquitin-immunoreactive inclusions were present in PCA-exposed rats, although they did not colocalize with alpha-synuclein. Western blotting performed at 6 months post PCA showed a reduction in the level of soluble alpha-synuclein compared with 1 month post PCA and the controls; this reduction was concomitant with an increase in the insoluble form of alpha-synuclein. Although the precise mechanism by which alpha-synuclein aggregates in PCA-treated rats remains unknown, the present data suggest an important role for this protein in the onset and progression of hepatic encephalopathy, probably via its expression in astroglial cells.

Induction of NOS and nitrotyrosine expression in the rat striatum following experimental hepatic encephalopathy

Hepatic encephalopathy (HE) is a neurologic disease associated with hepatic dysfunction. Astroglial and neuronal alterations have been described in the basal ganglia in HE. Our study was performed to determine whether such alterations are mediated by nitric oxide (NO), by using an experimental model of HE (portacaval anastomosis [PCA]). The expression of the NO synthases (nNOS and iNOS) and the production of nitrotyrosine (NT) were evaluated in the striatum of rats exposed to PCA for 1 and 6 months. The expression of nNOS in the striatal neurons of PCA rats was increased compared to controls. nNOS expression was also detectable in astrocytes after 6 months of exposure to PCA. Whereas astroglial cells in the normal striatum showed no iNOS expression, iNOS was expressed in the astrocytes of PCA brains, mainly in perivascular processes at 6 months PCA exposure (demonstrated by colocalization with GFAP). The increased expression of both the nNOS and iNOS isoforms in PCA rats might indicate a critical role for NO in the pathomechanism of HE. To study the potential cell damage caused by NO, the deposition of NT in PCA-rats was analysed. Nitrotyrosine was detected in neurons although it was mainly seen in the astrocytes of PCA brains, in which double immunolabelling showed NT to be colocalized with GFAP. Thus, the present study shows the induction of iNOS and NT in astrocytes, which increases with the duration of PCA exposure. This suggests that the induced astroglial production of NO during PCA might be one of the main factors contributing to HE.

The expression of nNOS, iNOS and nitrotyrosine is increased in the rat cerebral cortex in experimental hepatic encephalopathy

The changes in the distribution and amount of nitric oxide (NO) synthases (nNOS and iNOS) and the appearance of nitrotyrosine (NT) in the rat cerebral cortex were investigated following portacaval anastomosis (PCA), an experimental hepatic encephalopathy (HE) model. One month after PCA, rats showed more neurones immunoreactive to nNOS than did control animals. At 6 months post PCA, the number of neurones expressing nNOS had again increased and the intensity of the immunoreactions was stronger. Immunohistochemical analysis also showed that iNOS was increasingly expressed in pyramidal-like cortical neurones and in perivascular astrocytes from 1 to 6 months post PCA. In addition, a significant increase in cerebral iNOS concentration, at both post-PCA periods, was determined by Western blotting. The iNOS induction appears to be correlated with the length of the post-PCA period. PCA also induced the expression of NT, a nitration product of peroxynitrite. NT immunoreactivity was found in pyramidal-like cortical neurones. At 6 months, NT immunoreactivity was also evident in perivascular astrocytes, which was concomitant with a significant increase in NT protein level. PCA therefore not only increases the expression of nNOS but also induces the expression of iNOS and NT in both neurones and astrocytes. Taken together, these findings indicate that the induction of iNOS in pyramidal neurones and cortical astrocytes 6 months after PCA contributes to the generation of NT, and demonstrate the clear participation of NO in the pathogenic process of HE in this model.

374 Experimental hepatic encephalopathy improves after delivery of combined gene therapy (Ad-MMP8 plus Ad-huPA)

374 Experimental hepatic encephalopathy improves after delivery of combined gene therapy (Ad-MMP8 plus Ad-huPA)

Neuronal and inducible nitric oxide synthase expression in the rat cerebellum following portacaval anastomosis

In order to determine the role of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in the pathogenesis of experimental hepatic encephalopathy (HE), the expression of both was analyzed in the cerebellum of rats 1 month and 6 months after performing portacaval anastomosis (PCA). In control cerebella, nNOS immunoreactivity was mainly observed in the molecular layer (ML), whereas the Purkinje cells did not express nNOS. However, nNOS expression was detected in the Purkinje cells at 1 month after PCA, correlating with a decrease in nNOS expression in the ML — part of an overall reduction in cerebellar nNOS concentrations (as determined by Western blotting). At 6 months post-PCA, a significant increase in nNOS expression was observed in the ML, as well as increased nNOS immunoreactivity in the Purkinje cells. nNOS immunoreactivity was also observed in the Bergmann glial cells of PCA-treated rats. While no immunoreactivity for iNOS was seen in the cerebella of control rats, iNOS immunoreactivity was significantly induced in the cerebellum 1 month after PCA. In addition, the expression of iNOS was greater at 6 months than at 1 month post-PCA. Immunohistochemical analysis revealed this iNOS to be localized in the Purkinje cells and Bergmann glial cells. The induction of iNOS in astroglial cells has been associated with pathological conditions. Therefore, the iNOS expression observed in the Bergmann glial cells might play a role in the pathogenesis of HE, the harmful effects of PCA being caused by them via the production of excess nitric oxide. These results show that nNOS and iNOS are produced in the Purkinje cells and Bergmann glial cells following PCA, implicating nitric oxide in the pathology of HE.

373 Improved of experimental hepatic encephalopathy with delivery of combined gene therapy (ad-huPA+ad-MMP8)

373 Improved of experimental hepatic encephalopathy with delivery of combined gene therapy (ad-huPA+ad-MMP8)

Effects on drug disposition, brain monoamines and behavior after chronic treatment with the antidepressant venlafaxine in rats with experimental hepatic encephalopathy

Patients with chronic hepatic encephalopathy (HE) may present affective symptoms and antidepressant drug treatment in this condition is not uncommon. The present microdialysis study investigated treatment with the chronic antidepressant venlafaxine (VEN) in experimental HE with regard to tentative changes in pharmacokinetic and/or pharmacodynamic parameters. Three weeks after portacaval shunt (PCS) or sham operation in rats, VEN (10 mg/kg daily) was administered by implanted osmotic minipumps. VEN treatment for 14 days resulted in higher concentrations of VEN in PCS rats than in sham controls in serum and brain compartments, and the VEN levels in serum and brain were strongly inter-correlated. The serum N-desmethylvenlafaxine concentration did not differ between the groups, but correlated with the serum VEN levels. The other VEN metabolites were below the quantification limits. VEN treatment for 9–12 days significantly stimulated locomotion and rearing in the open field in sham controls, but failed to do so in the PCS rats. The concentrations of noradrenaline, dopamine, 5-HT, and 5-HIAA in neocortical dialysates were higher in PCS than in sham rats after 14 days of VEN treatment, but the elevations reached statistical significance only in the case of dopamine and 5-HIAA. In summary, there were significant pharmacokinetic and pharmacodynamic alterations in rats with experimental HE as compared to controls. The described experimental HE model may be useful for continued pharmacokinetic/pharmacodynamic interaction studies to unravel the pathophysiological consequences of HE on the CNS.

Effect of halving the dose of venlafaxine to adjust for putative pharmacokinetic and pharmacodynamic changes in an animal model of chronic hepatic encephalopathy.

Patients with chronic hepatic encephalopathy display monoaminergic perturbations together with affective symptoms. Thus, these patients belong to a group with a probability of receiving antidepressant drug treatment. The liver impairment may result in pharmacokinetic alterations of the antidepressant drug, which in turn may affect the already perturbed monoaminergic function. Venlafaxine (VEN) was administered as a single subcutaneous challenge to portacaval shunted (experimental hepatic encephalopathy model) rats (5 mg/kg) and sham-operated rats (5 and 10 mg/kg). The aims were to investigate whether a reduced dose in portacaval shunted rats resulted in higher concentrations of VEN and serotonin as compared to control rats, which had been demonstrated earlier when the rats received the same dose (10 mg/kg). A 50% reduction of the dose of VEN administered to portacaval shunted rats resulted in elevated levels of VEN in serum, brain parenchyma, and brain dialysate about 300 minutes after the injection. The VEN challenge increased the serotonin and noradrenaline concentrations in dialysate in portacaval shunted rats and both sham groups, but the three VEN groups did not differ in any major way in serotonin and noradrenaline output. Therefore, when the dose of VEN administered to experimental hepatic encephalopathy was reduced 50% as compared to control rats, mainly pharmacokinetic, and possibly also monoaminergic, alterations were observed.

Dynamic and kinetic effects of chronic citalopram treatment in experimental hepatic encephalopathy.

Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that arises in liver-impaired subjects. Patients with HE display various neuropsychiatric symptoms including affective disturbances and may therefore likely receive treatment with novel thymoleptics like citalopram (CIT). The simultaneous pharmacokinetic and pharmacodynamic outcome of the commonly used serotonin-selective thymoleptic drugs in liver-impaired subjects with pending chronic HE is far from understood today. We therefore investigated the effects of chronic, body-weight-adjusted (10 mg x kg(-1) x day(-1)), treatment with CIT in rats with and without portacaval shunts (PCS). Open-field activity was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) output were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were determined in serum, brain parenchyma, and extracellular fluid. The rats with PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham treatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the S/R ratios between PCS rats and control rats could be detected. The CIT treatment resulted in neocortical output differences between PCS rats and control rats mainly within the 5-HT and DA systems but not within the NA system. For the 5-HT system, this change was further evidenced by outspoken elevation in 5-HT output after KCI-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT treatment resulted in an increased or "normalized" behavioral activity in the PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in control rats. The results further support the contention of an altered 5-HT neurotransmission prevailing in the chronic HE condition. However, the tentatively beneficial behavioral response also seen following chronic CIT treatment to PCS rats in this study has to be viewed in relation to both the pharmacokinetic and pharmacodynamic changes observed.

Psychopharmacological aspects on monoaminergic and behavioral perturbations in experimental chronic hepatic encephalopathy

Psychopharmacological aspects on monoaminergic and behavioral perturbations in experimental chronic hepatic encephalopathy

Altered adaptive behaviour expressed in an open-field paradigm in experimental hepatic encephalopathy

Chronic hepatic encephalopathy (HE) encounters a neuropsychiatric syndrome arising as a complication to liver dysfunction. Patients with chronic HE display a great variety of neuropsychiatric symptoms including such mental derangements as adaptational difficulty, and deteriorated learning and memory capacity. The portacaval shunt (PCS) in the rat is a widely used model for experimental chronic HE. In the present study, the adaptive capacity of unhabituated PCS rats and sham-operated control rats were studied by measuring two exploratory behaviours (locomotion and rearing) during 5 or 60 min, at four consecutive days or nights with 24 h between sessions. The results revealed that PCS and sham-operated control rats showed parallel behavioural outcome over the four sessions in the 5-min trial. However, at the four consecutive test sessions in the 60-min trials, the sham-controls displayed a continuing decrease in overall activity between sessions whereas the PCS rats evidenced a repeated and stable activity level. These results indicate a presence of a long-term habituation deficiency as exhibited by the PCS rats. Additionally, the results indicate that differences in normal open-field motor behaviour between PCS rats and controls may not be found if such tests are conducted repeatedly during night-time but may emerge when tested repeatedly during daytime. The results may also be interpreted as a possible impaired learning/memory capacity in PCS rats. However, further investigations of how the PCS procedure affects entities of adaptation and learning ability are needed before any conclusions may be drawn since this is the first report of such an impairment in experimental chronic HE when represented by the PCS rat.

Plasma and brain levels of oxindole in experimental chronic hepatic encephalopathy: effects of systemic ammonium acetate and L-tryptophan.

It has previously been shown that the neurodepressant L-tryptophan metabolite oxindole is increased in the blood and brain of rats with fulminant hepatic failure and in the blood of cirrhotic patients affected by chronic hepatic encephalopathy. In the present investigation, we found that oxindole levels were significantly increased in the blood and brain of portacaval-shunted rats, an animal model of chronic hepatic encephalopathy, compared with sham-operated controls. A further increase in plasma and brain oxindole content was found after oral administration of L-tryptophan (300 mg/kg) to both portacaval-shunted or sham-operated animals, while intraperitoneal injection of the amino acid did not modify oxindole content either in brain or blood. Ammonium acetate administration (4.0 mmol/kg, intraperitoneal) reversibly deteriorated the neurological status of portacaval-shunted animals, but did not modify, in a directly related manner, plasma and brain oxindole content. The present findings are in line with the possibility that oxindole may be an additional L-tryptophan-related candidate in the pathogenesis of chronic hepatic encephalopathy.

Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges.

Latent or manifest chronic hepatic encephalopathy (HE) symptomatology often includes affective symptoms. It is therefore warranted to investigate the functional outcome of novel antidepressants when chronic HE prevails. Portacaval shunt (PCS) in rats is a widely used experimental model for chronic HE, a neuropsychiatric syndrome accompanying liver dysfunction. HE is believed to arise from a primary alteration in neurotransmission in the CNS. PCS has been reported to increase the metabolism of serotonin in the brain, and thus the central serotonin nerve of PCS rats may contain more serotonin than normal. However, the functional relevance of this serotonergic alteration in terms of affecting behavioral performance of PCS rats has been only rarely studied. Locomotor and rearing activities were recorded in PCS and sham-operated control rats. A single subcutaneous challenge with saline versus either the mixed serotonin/noradrenaline reuptake inhibitor venlafaxine (10 mg x kg(-1)) or the selective serotonin reuptake inhibitor citalopram (5 mg x kg(-1)) were performed. The PCS-saline injected rats showed reduced locomotor and rearing activity compared with sham-saline treated rats. While no significant differences could be observed following the venlafaxine challenge to controls, the PCS-venlafaxine challenged rats displayed reduced behavioral activity as compared to PCS-saline treated rats. The PCS-citalopram rats, however, displayed increased activity compared with the PCS-saline rats while, again, no effect of the citalopram challenge to controls was found. The present study show altered but opposite behavior in PCS rats, when challenged with either venlafaxine or citalopram, compared to PCS control rats. These findings therefore support the contention that caution should be advocated when CNS monoamine active drugs are used in liver-impaired subjects until better delineation of the combined pharmacodynamic and pharmacokinetic outcome for each such drug in this condition has been made.