L Vorobiev's 8 research works with citations and reads, including: Beta- carotene as a Novel Therapy for the Treatment of “Autistic Like Behavior” in. [PubMed]; Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM. Cannabidiol ameliorates cognitive and motor impairments in mice with bile. We aimed to demonstrate the involvement of 5-HT(1A) receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a.
CBD did not affect the activity of control animals. Locomotor function, evaluated 3 days after induction of hepatic failure, was decreased in thioacetamide TAA mice and was restored by cannabidiol CBD.
CBD did not affect the cognitive function of control animals. Cognitive function, tested 8 days after induction of hepatic failure, was impaired following thioacetamide TAA and was improved by cannabidiol CBD.
AUC, area under the curve. Overall, it seems that TAA administration increased the number of activated astrocytes and CBD significantly reduced this effect.
However, astrocytes in both CBD- and vehicle-treated TAA animals did not differ as regards their cellular size or extension of processes.
However, in the case of animals with hepatic encephalopathy, CBD treatment induced significant reduction in the total number of activated astrocytes, although the level of individual cell activation was not impaired. TAA-treated animals showed the typical TAA-induced liver necrosis lesions that have been described in detail previously Avraham et al. The statistical analysis of liver histopathology scores did not reveal significant differences in the extent and severity of necrotic lesions between CBD-treated and untreated mice data not shown.
CBD did not affect the levels of 5-HT in control animals. Brain 5-HT levels, measured 12 days after induction of hepatic failure, were increased in the brains of thioacetamide TAA mice and were restored by cannabidiol CBD. TAA only for all parameters. CBD did not affect the levels of any of these substances in control animals.
Indices of liver function. The hepatotoxicity of TAA is due to the generation of free radicals and oxidative stress Zimmermann et al. However, it is not clear whether TAA affects the brain directly or the liver Albrecht et al. Our results indicated that it has a neuroprotective role in HE induced by FHF; CBD was found to restore liver function, normalize 5-HT levels and improve the brain pathology in accordance with normalization of brain function. We also showed that CBD affects both central functions: Therefore, we conclude that it acts both centrally and peripherally.
In addition, it has been shown that CBD can cross the blood — brain barrier and act centrally for review see Pertwee, Therefore, its effect may result from a combination of its actions in the liver and the brain. However, to elucidate its mechanism of action future experiments are needed to determine the effects of central administration of CBD. Previous work from our laboratory has demonstrated an impaired neurological and motor function 3 days, and impaired cognition 12 days after TAA injection to mice Avraham et al.
These results were reproduced in the present study Figures 1—3. In a more recent study from our laboratory, cognitive and motor deficits were observed 21 days after bile duct ligation, a chronic model of liver disease Magen et al. The different durations of the development of HE symptoms in the two models apparently result from their different characteristics — an acute versus a chronic model of HE. In the latter model, CBD was found to improve cognition and locomotor activity, in accordance with our present data Magen et al.
However, in sharp contrast to the findings reported here no evidence for astrogliosis was found in that study data not reported ; in our acute model induced by TAA we observed astrogliosis after 3 days Figure 4C. Similar results were reported by Jover et al. In the work of Jover et al. The reason for this may be that in chronic liver disease induced by bile duct ligation, compensation mechanisms are activated, which moderate the brain damage, while in the acute model induced by TAA, no such mechanisms can come into action because of the severity of the liver insult and the short interval of time between the induction of liver damage and the histopathological examination.
Therefore, it is conceivable that such a mechanism was responsible for the astrogliosis observed in our study, since we found evidence of liver inflammation data not shown. As evident from the histopathology results, CBD did not appear to affect the development of TAA-induced necrotic lesions in the liver of mice. However, the levels of liver transaminases in the serum of CBD-treated mice were significantly reduced compared to their untreated counterparts, indicating that this substance contributed to a partial restoration of liver function.
Recent evidence elucidating the complicated mechanisms involved in the release of hepatocyte cytosolic enzymes such as ALT and AST in the blood may explain the discrepancy between histopathology and serum biochemistry data observed in the present study. Indeed, it is now generally accepted that the release of cytosolic enzymes during both the reversible and irreversible phases of hepatocyte injury and therefore their appearance in blood does not necessarily indicate cell death and also that enzyme release during reversible cell damage occurs with an apparent lack of histological evidence of necrosis Solter, The interaction between hyperammonaemia and inflammation as a precipitating factor for HE has been discussed in two recent reviews Shawcross and Jalan, ; Wright and Jalan, Astrogliosis has also been shown to be involved in learning and memory deficits in a mouse model of Alzheimer's disease.
In this study, astrogliosis was reduced by caloric restriction, which also reversed the cognitive deficits and increased the expression of neurogenesis in related genes Wu et al. Further studies, such as expression analysis of such genes using DNA microarray and evaluation of neurogenesis using BrdU staining, needs to be performed in order to explore the mechanisms through which TAA-induced astrogliosis impairs cognition, and through which CBD acts to improve it.
Even though astrogliosis was found a week before cognitive function was observed, and it is not definite whether it was long-lasting, this mechanism seems, in our eyes, to account for the cognitive dysfunction, rather than the increase in 5-HT level Figure 5. The latter mechanism does not seem to be related to the cognitive dysfunction, even though this increase in 5-HT was reversed by CBD Figure 5 , as 5-HT depletion, not increase, has been shown to cause memory deficits in the eight arm maze Mazer et al.
In addition, there is indirect evidence that this increase is related to decreased motor activity, as the nonselective 5-HT receptor antagonist methysergide increased motor activity in TAA-injected rats, while the selective 5-HT 2 receptor antagonist seganserin did not Yurdaydin et al. In parallel, motor activity was decreased following TAA injection and increased after CBD treatment, indicating a link between the increase in 5-HT and decrease in motor activity.
In our previous studies we showed that cognition is multifactorial and not dependent only on 5-HT levels, and therefore there is no direct correlation between cognition and 5-HT levels.
The reversal of astrogliosis was probably related to reduced hepatic toxin formation. Neurological and motor functions were improved 2 and 3 days, respectively, after induction of hepatic failure at the same time as a partial reversal of the astrogliosis and reduced levels of ammonia, bilirubin and liver enzymes were noticed. It seems that the behavioural effects of CBD are dramatic and occur within 3 days.
It appears that this effect of CBD is multifactorial and involves cannabinoid Avraham et al. CBD improves the symptoms of FHF by affecting both brain histopathology and liver function, and thus may serve as therapeutic agent for treating human HE.
Teaching Materials; Figs 1—6 as PowerPoint slide. National Center for Biotechnology Information , U. Journal List Br J Pharmacol v. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Introduction Hepatic encephalopathy HE is a syndrome observed in patients with end-stage liver disease. Methods Mice Female Sabra mice 34—36 g , 8 to 10 weeks old, were assigned at random to different groups of 10 mice per cage and were used in all experiments.
Induction of hepatic failure We adapted the rat model of acute liver failure induced by TAA to mice Zimmermann et al. Administration of CBD CBD was extracted from cannabis resin hashish and purified as previously reported Gaoni and Mechoulam, and was dissolved in a vehicle solution consisting of ethanol, emulphor and saline at a ratio of 1: Assessment of neurological function Neurological function was assessed by a point scale based on reflexes and task performance Chen et al.
Assessment of activity The activity test was performed 2 days after the induction of hepatic failure. Cognitive function Cognitive function studies were performed 8 days after the induction of hepatic failure. Serum ammonia, liver enzymes and bilirubin levels Serum for alanine transaminase ALT , aspartate transaminase AST , bilirubin and ammonia measurements was obtained on day 3 in glass tubes, centrifuged, and analysed on the day of sampling using a Kone Progress Selective Chemistry Analyzer Kone Instruments, Espoo, Finland.
Experiment 2 This was identical to experiment 1 on days 1—3, only the mice were not killed on day 3 but were evaluated for cognitive function using the eight-arm maze test, on days 8— Results Neurological score TAA significantly increased the neurological score of mice compared to the control group Figure 1 ; one-way anova: Open in a separate window.
Activity TAA decreased the activity level of the mice Figure 2 ; anova: Acknowledgments We would like to thank the Israel Science Foundation for their support. Conflict of interest None.
Supplementary material Supporting Information: Click here to view. Contrasting effects of thioacetamide-induced liver damage on the brain uptake indices of ornithine, arginine and lysine: Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice. Cannabinoids and Capsaicin improve liver function following Thioacetamide — induced acute injury in mice. Prostaglandins Leukot Essent Fatty Acids. Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice.
Inhibition of an equilibrative nucleoside transporter by cannabidiol: Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy: An experimental model of closed head injury in mice: Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury.
Thioacetamide-induced liver regeneration involves the expression of cyclooxygenase 2 and nitric oxide synthase 2 in hepatocytes. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. The isolation and structure of deltatetrahydrocannabinol and other neutral cannabinoids from hashish.
J Am Chem Soc. Separation-induced body weight loss, impairment in alternation behavior, and autonomic tone: Interaction of oxidative stress, astrocyte swelling and cerebral ammonia toxicity. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Administration of 8-hydroxy Di-n-propylamino tetralin in raphe nuclei dorsalis and medianus reduces serotonin synthesis in the rat brain: Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: Separation as a new animal model for self-induced weight loss.
Endocannabinoids in liver disease and hepatic encephalopathy. Cannabidiol ameliorates cognitive and motor impairments in mice with bile duct ligation. Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT 1A receptor activation.
The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Effect of sulphur dioxide and thermal treatments, Journal of Food Engineering, , doi: Compressing behaviour and texture evaluation for potatoes pretreated by pulsed electric field.
Journal of texture studies, 40 2 , Solid-liquid expression from denaturated plant tissue: Filtration-consolidation behaviour, Journal of Food Engineering, , doi: Technology, , 26 2 , Influence of particle concentration and presence of dispersant, Colloids and Surfaces A: Physicochemical and Engineering Aspects, , , Osmotic dehydration of carrot tissue enhanced by pulsed electric field, salt and centrifugal force, Journal of Food Engineering, , 83 4 , Centrifugal osmotic dehydration of carrot tissues pre-treated by pulsed electric field, LWT Food Science and Technology, , 40 7 , El-Belghiti K, Rabhi Z.
Effect or process parameters on solute centrifugal extraction from electropermeabilized carrot gratings, Food and Bioproducts Processing, , 87 1C , Influence of temperature and surfactant on Escherichia coli inactivation in aqueous suspensions treatedby moderate pulsed electric fields, International Journal of Food Microbiology, , In press. Pulsed electric field enhanced drying of potato tissue, Journal of Food Engineering, , 78 2 , Pulsed electric fields and thermal treatment, Journal of Food Engineering, , 80 2 , Moderate electric field treatment of sugarbeet tissues, Biosystems Engineering, , 96 1 , Lebovka NI, Vorobiev E.
The kinetics of inactivation of spheroidal microbial cells by pulsed electric fields, Archive, Physics, , Analysis of juice colour and dry matter content during pulsed electric field enhanced expression of soft plant tissues, Journal of Food Engineering, , 79 2 , Pulsed electric field enhanced expression and juice quality of white grapes, Separation and Purification Technology, , 52 3 , Modelling of mass transfer during osmotic dehydration of apple tissue pre-treated by pulsed electric field, LWT- Food Science and Technology, , 39 9 , The early stages of Saccharomyces cerevisiae yeast suspensions damage in moderate pulsed electric fields.
Colloids and Surfaces B: Biointerfaces, , 47 2 , Behavior of yeast cells in aqueous suspension affected by pulsed electric field, Journal of Colloid and Interface Science, , 2 , Drying of potato tissue pretreated by ohmic heating, Drying Technology, 24, , — Aspects, , , Ghnimi, S et Vorobiev, E.
IChemE, , 82 C3 , IChemE, , 82 A1 , IChemE, , 81, Part A, Effect of moderate electric field pulses on the diffusion coefficient of soluble substances from apple slices. International Journal of Food Science and Technology, , 37, Visualization of percolative properties", Innovative Food Sci.
Electrical treatment of apple cossettes for intensifying juice pressing, J. Beet juice extraction by pressing and pulsed electric fields, International Sugar Journal, CII , pp Journal of Food Engineering, 44, Filtration-consolidation analysis of solid-liquid expression from biological tissue. Filtration of highly concentrated CaCO3 suspensions using a rotating disk dynamic system.
Dead-end filtration of Saccharomyces cerevisiae yeast suspensions: Improvement of polyphenols extraction from grape pomace using pulsed arc electro. High voltage electrical discharges:
High Energy Physics - Phenomenology
Abstract: BACKGROUND AND PURPOSE: Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver. Vorobiev L, eight arm maze test, and neurotransmitter (norepinephrine, dopamine, L-DOPA and serotonin) SRA normalized NE and L-DOPA levels. Amami, E. ; Vorobiev, E. ; Kechaou, N. Effect of pulsed electric field on the Daudin, J.D. Calcul des cinétiques de séchage par l'air chaud des produits.