RESUMEN
We have investigated the effects of 0.001mg/kg 2-arachidonoylglycerol (2-AG) administered in combination with compounds present in the body alongside 2-AG like 2-palmitoylglycerol and 2-linoleylglycerol (also termed "entourage"), on cognitive function,food intake, and neurotransmitter levels in the hippocampus and hypothalamus of mice under diet restriction. Young female Sabra mice were treated with vehicle, 2-AG, 2-AG+entourage, 2-AG+entourage+5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716A, a CB1 antagonist) and SR141716A. The mice were fed for 2.5h a day for 14days. Cognitive function was evaluated by the eight arm maze test, and neurotransmitter (norepinephrine, dopamine, L-DOPA and serotonin) levels were measured in the hippocampus and hypothalamus by high-performance liquid chromatography-electrochemical detection. Food intake was increased by 2-AG and, to an even greater extent, by 2-AG+entourage. SR141716A reversed the effect of 2-AG+entourage. The administration of 2-AG+entourage improved cognitive function compared to the vehicle mice, and this improvement was blocked by SR141716A. 2-AG+entourage-treated mice showed an increase in norepinephrine (NE), dopamine and L-DOPA levels in the hippocampus. SR141716A normalized NE and L-DOPA levels. There were no significant changes in hypothalamic neurotransmitter levels. The use of very low doses of the endocannabinoid 2-AG+entourage can improve cognitive function by elevating norepinephrine and L-DOPA levels in the hippocampus, without cannabinomimetic side effects. These findings may have implications for cognitive enhancement in anorexia nervosa.
Asunto(s)
Anorexia Nerviosa/tratamiento farmacológico , Ácidos Araquidónicos/farmacología , Endocannabinoides/farmacología , Glicéridos/farmacología , Animales , Moduladores de Receptores de Cannabinoides/farmacología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Levodopa/farmacología , Ratones , Neurotransmisores/farmacología , Distribución AleatoriaRESUMEN
Activity-dependent neuroprotective protein (ADNP) is a most frequent autism spectrum disorder (ASD)-associated gene and the only protein significantly decreasing in the serum of Alzheimer's disease (AD) patients. Is ADNP associated with ASD being more prevalent in boys and AD more prevalent in women? Our results revealed sex-related learning/memory differences in mice, reflecting hippocampal expression changes in ADNP and ADNP-controlled AD/ASD risk genes. Hippocampal ADNP transcript content was doubled in male vs female mice, with females showing equal expression to ADNP haploinsufficient (ADNP(+/)(-)) males and no significant genotype-associated reduction. Increased male ADNP expression was replicated in human postmortem hippocampal samples. The hippocampal transcript for apolipoprotein E (the major risk gene for AD) was doubled in female mice compared with males, and further doubled in the ADNP(+/-) females, contrasting a decrease in ADNP(+/-) males. Previously, overexpression of the eukaryotic translation initiation factor 4E (eIF4E) led to ASD-like phenotype in mice. Here, we identified binding sites on ADNP for eIF4E and co-immunoprecipitation. Furthermore, hippocampal eIF4E expression was specifically increased in young ADNP(+/-) male mice. Behaviorally, ADNP(+/-) male mice exhibited deficiencies in object recognition and social memory compared with ADNP(+/+) mice, while ADNP(+/-) females were partially spared. Contrasting males, which preferred novel over familiar mice, ADNP(+/+) females showed no preference to novel mice and ADNP(+/-) females did not prefer mice over object. ADNP expression, positioned as a master regulator of key ASD and AD risk genes, introduces a novel concept of hippocampal gene-regulated sexual dimorphism and an ADNP(+/-) animal model for translational psychiatry.
Asunto(s)
Enfermedad de Alzheimer/genética , Trastorno Autístico/genética , Conducta Animal , Hipocampo/metabolismo , Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso/genética , ARN Mensajero/metabolismo , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Femenino , Perfilación de la Expresión Génica , Heterocigoto , Humanos , Masculino , Memoria , Ratones , Reconocimiento en Psicología , Factores Sexuales , Conducta SocialRESUMEN
BACKGROUND: Prevalent non-motor symptoms of Parkinson's disease (PD) include gastrointestinal motor impairments and advanced stage PD displays pathological aggregates of α-synuclein in colonic enteric neurons. We previously showed that 12 months old mice overexpressing human wild type (WT) α-synuclein under the Thy1 promoter (Thy1-aSyn) displayed colonic motor dysfunction. We investigated functional gut alterations at earlier ages and histological correlates. METHODS: Defecation, gastric emptying (GE), and immunostaining for α-synuclein, peripheral choline acetyltransferase (pChAT), tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) in distal colon myenteric plexuses were assessed in male Thy1-aSyn compared to littermate WT mice. KEY RESULTS: Thy1-aSyn mice aged 2.5-3 or 7-8 months old had 81% and 55% reduction in fecal pellet output, respectively, in the first 15 min of exposure to a novel environment. The reduction remained significant in the older group for 2-h, and subsequent refeeding resulted also in a 60% and 69% reduction of defecation in the first hour, respectively. Thy1-aSyn mice (8-10 months) displayed increased α-synuclein in the myenteric plexuses with abundant varicose terminals surrounding pChAT-immunoreactive (ir) neurons, and only a few, nNOS-ir neurons. There were no conspicuous changes in pChAT- and nNOS-ir neurons, or TH- and VIP-ir nerve fibers. Thy1-aSyn mice aged 4-18 months had normal GE. CONCLUSIONS & INFERENCES: The occurrence of over-production of pre-synaptic α-synuclein in colonic myenteric ganglia several months before the loss of striatal dopamine may provide an anatomical basis for interference with cholinergic neuronal activation, causing an early impairment in defecation to stimuli.
Asunto(s)
Colon/fisiología , Defecación/fisiología , Ganglios Autónomos/metabolismo , Plexo Mientérico/metabolismo , alfa-Sinucleína/metabolismo , Animales , Colina O-Acetiltransferasa/metabolismo , Colon/inervación , Colon/fisiopatología , Ganglios Autónomos/fisiopatología , Vaciamiento Gástrico/fisiología , Masculino , Ratones , Ratones Transgénicos , Plexo Mientérico/fisiopatología , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH: Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS: Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS: Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain.
Asunto(s)
Encéfalo/efectos de los fármacos , Cannabidiol/farmacología , Encefalopatía Hepática/tratamiento farmacológico , Fallo Hepático Agudo/tratamiento farmacológico , Hígado/efectos de los fármacos , Amoníaco/sangre , Animales , Bilirrubina/sangre , Encéfalo/patología , Encéfalo/fisiopatología , Cognición/efectos de los fármacos , Femenino , Encefalopatía Hepática/metabolismo , Encefalopatía Hepática/fisiopatología , Hígado/patología , Hígado/fisiopatología , Fallo Hepático Agudo/metabolismo , Fallo Hepático Agudo/fisiopatología , Ratones , Actividad Motora/efectos de los fármacos , Distribución Aleatoria , Receptores de Serotonina/metabolismo , Tioacetamida/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: 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 model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice. EXPERIMENTAL APPROACH: Cannabidiol (5 mg x kg(-1); i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-alpha receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT(1A) receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT(1A) receptor antagonist (0.5 mg x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin. KEY RESULTS: Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT(1A) expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT(1A) receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL. CONCLUSIONS AND IMPLICATIONS: The behavioural outcomes of BDL result from both 5-HT(1A) receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT(1A) receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.
Asunto(s)
Antiinflamatorios/farmacología , Conducta Animal/efectos de los fármacos , Cannabidiol/farmacología , Colestasis Extrahepática/tratamiento farmacológico , Cognición/efectos de los fármacos , Encefalopatía Hepática/prevención & control , Hipocampo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Colestasis Extrahepática/complicaciones , Colestasis Extrahepática/metabolismo , Colestasis Extrahepática/fisiopatología , Colestasis Extrahepática/psicología , Conducto Colédoco/cirugía , Modelos Animales de Enfermedad , Antagonistas de Dopamina/farmacología , Femenino , Encefalopatía Hepática/etiología , Encefalopatía Hepática/metabolismo , Encefalopatía Hepática/fisiopatología , Encefalopatía Hepática/psicología , Hipocampo/metabolismo , Ligadura , Hígado/fisiopatología , Pruebas de Función Hepática , Ratones , ARN Mensajero/metabolismo , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1RESUMEN
BACKGROUND AND PURPOSE: Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy. EXPERIMENTAL APPROACH: Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB(1), CB(2) and TRPV1 receptor agonist); HU308 (CB(2) receptor agonist), SR141716A (CB(1) receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB(2) receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively. RESULTS: Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin. CONCLUSIONS: Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.