Lactobacillus rhamnosusGG reduces hepatic fibrosis in a model of chronic liver disease in rats

BACKGROUND: The intestinal dysbiosis is common in chronic liver disease and can induce to inflammatory responses and mediate the collagen deposition in the liver. AIM: To evaluate the probiotic Lactobacillus rhamnosus GG (LGG) for the treatment of liver fibrosis in a model of chronic cholestatic liver disease in rats. METHODS: Male adult Wistar rats (n = 29) were submitted to common bile duct ligation (BDL groups) or manipulation of common bile duct without ligation (Ctrl groups).Two weeks after surgery, each group was randomly divided to receive 1 ml of PBS (Ctrl and BDL) or PBS containing 2.5 x 107 CFU of LGG (Ctrl-P and BDL-P) through gavages for 14 days. Euthanasia occurred 33 days after surgery when samples of blood and liver tissue were collected. RESULTS: The hepatic gene expression of Tlr4, Tnfα, IL-6, Tgfß, and metalloproteinase-2 and -9 were higher in the BDL groups in comparison to Ctrl. The ductular reaction evaluated by immunocontent of cytokeratin-7 (CK7) and the content of collagen were increased in BDL groups. Also, there was an imbalance in the antioxidant defenses (superoxide dismutase and catalase) and an increase in the oxidative stress marker sulfhydryl in BDL groups. The treatment with LGG significantly reduced gene expression of IL-6, collagen deposition, and ductular reaction in hepatic tissue of animals from BDL-P groups. CONCLUSION: The treatment with the probiotic LGG was able to reduce liver fibrosis, ductular reaction, and hepatic gene expression of IL-6 in a model of cholestatic liver disease in rats.

Impairment of short term memory in rats with hepatic encephalopathy due to bile duct ligation.

Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to cognitive deficits. Different animal models for the study of HE have demonstrated learning and memory impairment and a number of neurotransmitter systems have been proposed to be involved in this. Recently, it was described that bile duct-ligated (BDL) rats exhibited altered spatio-temporal locomotor and exploratory activities and biosynthesis of neurotransmitter GABA in brain cortices. Therefore, the aim of this study was to evaluate cognition in the same animal model. Male adult Wistar rats underwent common bile duct ligation (BDL rats) or manipulation of common bile duct without ligation (control rats). Six weeks after surgery, control and BDL rats underwent object recognition behavioral task. The BDL rats developed chronic liver failure and exhibited a decreased discrimination index for short term memory (STM) when compared to the control group. There was no difference in long term memory (LTM) as well as in total time of exploration in the training, STM and LTM sessions between the BDL and control rats. Therefore, the BDL rats demonstrated impaired STM for recognition memory, which was not due to decreased exploration.

Impairment of the organization of locomotor and exploratory behaviors in bile duct-ligated rats.

Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to several problems, including motor impairment. Animal models of chronic liver disease have extensively investigated the mechanisms of this disease. Impairment of locomotor activity has been described in different rat models. However, these studies are controversial and the majority has primarily analyzed activity parameters. Therefore, the aim of the present study was to evaluate locomotor and exploratory behavior in bile duct-ligated (BDL) rats to explore the spatial and temporal structure of behavior. Adult female Wistar rats underwent common bile duct ligation (BDL rats) or the manipulation of common bile duct without ligation (control rats). Six weeks after surgery, control and BDL rats underwent open-field, plus-maze and foot-fault behavioral tasks. The BDL rats developed chronic liver failure and exhibited a decrease in total distance traveled, increased total immobility time, smaller number of rearings, longer periods in the home base area and decreased percentage of time in the center zone of the arena, when compared to the control rats. Moreover, the performance of the BDL rats was not different from the control rats for the elevated plus-maze and foot-fault tasks. Therefore, the BDL rats demonstrated disturbed spontaneous locomotor and exploratory activities as a consequence of altered spatio-temporal organization of behavior.

Interleukin-6 serum levels in patients with Parkinson's disease.

Several lines of evidence suggest that neuroimmune mechanisms may be involved in the neurodegenerative process of Parkinson's disease (PD). Interleukin-6 (IL-6) is increased in the nigrostriatal region and in the cerebrospinal fluid of patients with PD. IL-6 serum level was evaluated in PD patients. The effects of levodopa treatment and disease severity on IL-6 were also studied. The IL-6 levels were similar between PD patients (treated and not treated) and controls. However, there was a negative correlation of IL-6 levels and the activities of daily living scale (P < 0.05), indicating that patients with more severe disease have higher levels of this cytokine. No correlation involving levodopa treatment and IL-6 serum level was found. The results suggest that only marginal effects of IL-6 occur on the peripheral immune system, and that the role of IL-6 and others neuroimmune factors needs to be well elucidated on PD.

Antinociceptive effects of intracerebroventricular administration of guanine-based purines in mice: evidences for the mechanism of action.

It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines (GBPs) on pain transmission. The aim of this study was to investigate the effects of intracerebroventricular (i.c.v.) guanosine and GMP on mice pain models. Mice received an i.c.v. injection of vehicle (saline or 10 muM NaOH), guanosine (5 to 400 nmol), or GMP (240 to 960 nmol). Additional groups were also pre-treated with i.c.v. injection of the A(1)/A(2A) antagonist caffeine (15 nmol), the non-selective opioid antagonist naloxone (12.5 nmol), or the 5'-nucleotidase inhibitor AOPCP (1 nmol). Measurements of CSF purine levels and cortical glutamate uptake were performed after treatments. Guanosine and GMP produced dose-dependent antinociceptive effects. Neither caffeine nor naloxone affected guanosine antinociception. Pre-treatment with AOPCP completely prevented GMP antinociception, indicating that conversion of GMP to guanosine is required for its antinociceptive effects. Intracerebroventricular administration of guanosine and GMP induced, respectively, a 180- and 1800-fold increase on CSF guanosine levels. Guanosine was able to prevent the decrease on cortical glutamate uptake induced by intraplantar capsaicin. This study provides new evidence on the mechanism of action of GBPs, with guanosine and GMP presenting antinociceptive effects in mice. This effect seems to be independent of adenosine and opioid receptors; it is, however, at least partially associated with modulation of the glutamatergic system by guanosine.

Pentylenetetrazol kindling alters adenine and guanine nucleotide catabolism in rat hippocampal slices and cerebrospinal fluid.

Pentylenetetrazol (PTZ) is commonly used as a convulsant drug. The enhanced seizure susceptibility induced by kindling is probably attributable to plastic changes in the synaptic efficacy. Adenosine and guanosine act both as important neuromodulators and neuroprotectors with mostly inhibitory effects on neuronal activity. Adenosine and guanosine can be released per se or generated from released nucleotides (ATP, ADP, AMP, GTP, GDP, and GMP) that are metabolized and rapidly converted to adenosine and guanosine. The aim of this study was to evaluate nucleotide hydrolysis by ecto- and soluble nucleotidases (hippocampal slices and CSF, respectively) after PTZ-kindling (stages 3, 4, or 5 seizures) or saline treatment in rats. Additionally, the levels of purines in rat cerebrospinal fluid (CSF), as well as ecto-NTPDases (1, 2, 3, 5, 6 and 8) and ecto- 5'-nucleotidase expression were determined. Ecto-enzyme assays demonstrated that ATP, AMP, GDP, and GMP hydrolysis enhanced when compared with controls. In addition, there was an increase of ADP, GDP, and GMP hydrolysis by soluble nucleotidases in PTZ-kindling rats compared to control group. The HPLC analysis showed a marked increase in PTZ-kindled CSF concentrations of GTP, ADP, and uric acid, but GDP, AMP, and hypoxanthine concentrations were decreased. Such alterations indicate that the modulatory role of purines in CNS could be affected by PTZ-kindling. However, the physiological significance of these findings remains to be elucidated.

Antidepressivos tricíclicos: uma revisão sobre os aspectos farmacológicos e a importância do monitoramento terapêutico / Tricycles antidepressants: a review about pharmacological characteristics and therapeutic dry monitoring importance

O monitoramento terapêutico é fundamental no acompanhamento de diversos tratamentos, pois permite avaliar se os níveis plasmáticos dos fármacos estão dentro do intervalo terapêutico possibilitando a melhora da resposta clínica e a diminuição da morbidez dos pacientes. Os antidepressivos tricíclicos (ADT) são exemplo de fármacos que necessitam monitoramento terapêutico, pois apresentam estreita faixa terapêutica, risco de toxicidade, metabólitos ativos e baixa correlação entre a dose administrada e níveis plasmáticos. Além disso, fatores como idade, outras patologias associadas e interações medicamentosas podem interferir nos níveis plasmáticos dos ADT. O objetivo deste trabalho foi revisar algumas características farmacológicas dos ADT assim como demonstrar a importância do monitoramento terapêutico para essa classe de fármacos

Biochemical brain markers and purinergic parameters in rat CSF after seizure induced by pentylenetetrazol.

Cellular and molecular mechanisms involved in the generation of seizures and the magnitude of neural cells injury are not fully understood. We evaluated astrocyte and/or neuronal injury in rats in the pentylenetetrazol model of acute seizures by measuring S100B and NSE levels in cerebrospinal fluid. Additionally, we determined ADP and GDP hydrolysis by soluble nucleoside triphosphate diphosphohydrolase in the cerebrospinal fluid, and the concentration of nucleosides adenosine, inosine and guanosine as putative markers of brain injury. After pentylenetetrazol-induced seizures: (i) S100B values increased from 10 to 30 min, returning to control levels at 24 h; NSE levels presented a biphasic increase: an increase at 10 to 30 min returning to control levels, and again at 240 min followed by a decline at 24 h; (ii) nucleotidase activities increased from 10 min, returning to control levels at 240 min; (iii) guanosine and inosine levels increased exclusively after 30 min. In summary, this study showed biochemical changes in the cerebrospinal fluid occurring after seizures induced by pentylenetetrazol. Such events may have a modulating effect upon seizure expression, particularly nucleoside triphosphate diphosphohydrolase activities and nucleoside concentrations, but are nevertheless followed by neural death as evidenced by the increase in NSE and S100B levels.