RESUMEN
An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on α-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to all experimental conditions, i.e., prenatal stress, acute stress, and glucose administration. Our data indicate that glycolysis is increased and the Krebs cycle is decreased in the brain of a prenatal stress animal model of depression.
Asunto(s)
Encéfalo/metabolismo , Depresión/patología , Glucosa/metabolismo , Administración Oral , Animales , Modelos Animales de Enfermedad , Femenino , Glucosa/administración & dosificación , Glucosafosfato Deshidrogenasa/metabolismo , Hexoquinasa/metabolismo , Ácido Láctico/metabolismo , Masculino , Mitocondrias/metabolismo , Mitocondrias/patología , Fosfofructoquinasas/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Piruvato Quinasa/metabolismo , Ácido Pirúvico/metabolismo , Ratas , Ratas Sprague-Dawley , Natación/psicologíaRESUMEN
RATIONALE: Recent clinical studies suggest GABA-ergic system abnormalities as a neuropathological mechanism of schizophrenia. OBJECTIVES: In the present study, we examined the effect of chronic prenatal lipopolysaccharide (LPS) administration on immunohistochemical changes of glutamate decarboxylase (GAD67) and parvalbumin (PV)-expressing neurons in the medial prefrontal cortex and hippocampus of rats. RESULTS: These data demonstrated that prenatal LPS administration during the final 2 weeks of pregnancy induced schizophrenia-like behavioral symptoms, such as deficits in sensorimotor gating (prepulse inhibition) and impairments in social interactions and exploration, in adult offspring. Moreover, immunohistochemical analysis revealed that in our neurodevelopmental model of schizophrenia, decreases in the total number of PV- and GAD67-positive neurons in the medial prefrontal cortices of adult females prenatally exposed to LPS were observed, whereas these immunochemical changes were primarily detected in the hippocampus of males. Additionally, a decrease in PV-labeled axon terminals of GABA-ergic cells, likely reflecting the perisomatic inhibitory innervation of pyramidal neurons, was observed in the medial prefrontal cortices in both sexes. CONCLUSION: This study provided evidence of a key role for the GABA system in neurodevelopment associated with the etiopathogenesis of schizophrenia and showed that the observed changes are sex-dependent. Moreover, this study is the first to present a model of schizophrenia based on prenatal LPS administration, which not only produced behavioral abnormalities but also changed the cytoarchitecture of the GABA inhibitory system.
Asunto(s)
Glutamato Descarboxilasa/metabolismo , Hipocampo/metabolismo , Parvalbúminas/metabolismo , Corteza Prefrontal/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Esquizofrenia/metabolismo , Animales , Recuento de Células , Conducta Exploratoria/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Inmunohistoquímica , Lipopolisacáridos/toxicidad , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/enzimología , Embarazo , Inhibición Prepulso/efectos de los fármacos , Ratas , Ratas Wistar , Esquizofrenia/inducido químicamente , Esquizofrenia/fisiopatología , Factores Sexuales , Conducta SocialRESUMEN
Depression is a mental disorder of still unknown origin. Currently, much attention is paid to the potential influence of disturbances in the functioning of neurotrophic factors on the onset of this disease. Insulin-like growth factor 1 (IGF-1) is one of the most important growth agents affecting processes that are crucial for brain development. To date, there are no data showing the impact of prenatal stress on the family of six IGF binding proteins (IGFBP 1-6) that regulate IGF-1 bioactivity. The goal of this study was to investigate whether the decreased expression of IGF-1 in the frontal cortex (FCx) and hippocampus (Hp) of adult male rats following a prenatal stress procedure is related to changes in the IGFBP family. Our results show that rats exposed prenatally to stressful stimuli displayed depression-like behavior based on sucrose preference and elevated plus maze tests. In both cases, in the adult rat brain structures that were examined after the prenatal stress procedure, the IGF-1 protein level was reduced. Moreover, we observed changes of varying degrees in the levels of IGFBPs in stressed animals. A decrease in IGFBP-2 and IGFBP-3 accompanied by an increase in the IGFBP-4 concentration in the Hp and the FCx was detected. There were no differences in IGFBP-1 and IGFBP-6 brain levels between the stressed and control animals, whereas IGFBP-5 concentration was decreased in the Hp of prenatally stressed animals. This study demonstrated that stress during pregnancy may lead not only to behavioral disturbances but also to a decrease in IGF-1 level and the dysregulation of the IGF-1 binding protein network in adult rat offspring.
Asunto(s)
Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Estrés Psicológico/metabolismo , Anhedonia/fisiología , Animales , Ansiedad/fisiopatología , Femenino , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/fisiopatologíaRESUMEN
Excessive glucocorticoid levels in depressed patients have been associated with atrophic changes in some brain regions, but only few studies suggest that some antidepressants can interfere with deleterious effect of glucocorticoids on neuronal cells. The aim of the present study was to examine the effect of dexamethasone (DEX), a synthetic glucocorticoid and some antidepressants from different chemical groups (imipramine, desipramine, amitriptyline, citalopram, fluoxetine, reboxetine and tianeptine) on SH-SY5Y cells cultured in the medium containing steroid-free serum. DEX in concentrations from 1 to 100 µM did not change LDH release but exposure to 10 µM and 100 µM DEX for 24, 48 and 72 h caused a significant reduction in cell viability and proliferation as confirmed by MTT reduction and BrdU ELISA assays, respectively. Twenty four-hour incubation of cells with antidepressants (0.05-10 µM) and DEX (10 µM) showed that imipramine, amitriptyline, desipramine, citalopram and fluoxetine at concentrations from 0.1 up to 1 µM, reboxetine (0.1 µM) and tianeptine (0.05 µM) prevented the DEX-induced decreases in cell viability and proliferation rate. The protective effects of antidepressants were ameliorated by inhibitors of MAPK/ERK1/2, but not PI3-K/Akt pathway as shown for imipramine, fluoxetine and reboxetine. Moreover, Western blot analysis showed the decrease in the activated form of ERK1/2 (p-ERK) after DEX treatment and this effect was inhibited by imipramine. Thus, the reduction in SH-SY5Y cell viability caused by DEX appears to be related to its antiproliferative activity and some antidepressant drugs in low concentrations attenuate this effect by mechanism which involves the activation of MAPK/ERK1/2 pathway.
Asunto(s)
Antidepresivos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dexametasona/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neuroblastoma/patología , Western Blotting , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Humanos , Neuroblastoma/enzimologíaRESUMEN
The aim of this study was to evaluate the effect of prenatal lipopolysaccharide (LPS) treatment, which is an animal developmental model of schizophrenia, on MK-801-induced psychotomimetic behavioral changes and brain aminergic system activity in adult offspring. Repeated LPS (1 mg/kg) injection in rats, that had started from 7th day of pregnancy and was continued every second day till delivery, resulted in a long-lasting disruption of prepulse inhibition (PPI) and elevation of locomotor activity in their offspring. The prenatally LPS-treated rats showed hypersensitivity to MK-801 (0.1 and 0.4 mg/kg) as evidenced by the enhancement of acoustic startle amplitude, reduced PPI, and enhanced locomotor activity. These behavioral changes were accompanied by a decrease in the dopamine and its metabolite, DOPAC concentration in the frontal cortex, enhanced dopaminergic system activity in the striatum and no changes in noradrenaline (NA) level. Furthermore, the significant augmentation of 5-HT and 5-HIAA content in the frontal cortex of females only was detected. No changes in the cortical NA tissue level were found. Summing up, the present study demonstrated that the activation of the immune system in prenatal period led to persistent behavioral hypersensitivity to psychotomimetic action of a non-competitive NMDA receptor antagonist, and attention/information processing deficits. The foregoing data indicate that prenatal administration of LPS model some of the clinical aspects of schizophrenia and these behavioral effects are connected with neurochemical changes.
Asunto(s)
Maleato de Dizocilpina/toxicidad , Alucinógenos/toxicidad , Lipopolisacáridos/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/administración & dosificación , Dopamina/metabolismo , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/toxicidad , Femenino , Alucinógenos/administración & dosificación , Humanos , Lipopolisacáridos/administración & dosificación , Masculino , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas Wistar , Esquizofrenia/etiología , Esquizofrenia/fisiopatología , Filtrado Sensorial/efectos de los fármacos , Serotonina/metabolismoRESUMEN
TRH (thyroliberin) and its analogues were reported to possess neuroprotective effects in cellular and animal experimental models of acute and chronic neurodegenerative diseases. In the present study we evaluated effects of TRH and its three stable analogues, montirelin (CG-3703), RGH-2202 and Z-TRH (N-(carbobenzyloxy)-pGlutamyl-Histydyl-Proline) on the neuronally differentiated human neuroblastoma SH-SY5Y cell line, which is widely accepted for studying potential neuroprotectants. We found that TRH and all the tested analogues at concentrations 0.1-50 µM attenuated cell damage induced by MPP(+) (2 mM), 3-nitropropionate (10 mM), hydrogen peroxide (0.5 mM), homocysteine (250 µM) and beta-amyloid (20µM) in retinoic acid differentiated SH-SY5Y cells. Furthermore, we demonstrated that TRH and its analogues decreased the staurosporine (0.5 µM)-induced LDH release, caspase-3 activity and DNA fragmentation, which indicate the anti-apoptotic proprieties of these peptides. The neuroprotective effects of TRH (10 µM) and RGH-2202 (10 µM) on St-induced cell death was attenuated by inhibitors of PI3-K pathway (wortmannin and LY294002), but not MAPK/ERK1/2 (PD98059 and U0126). Moreover, TRH and its analogues at neuroprotective concentrations (1 and 10 µM) increased expression of Bcl-2 protein, as confirmed by Western blot analysis. All in all, these results extend data on neuroprotective properties of TRH and its analogues and provide evidence that mechanism of anti-apoptotic effects of these peptides in SH-SY5Y cell line involves induction of PI3K/Akt pathway and Bcl-2. Furthermore, the data obtained on human cell line with a dopaminergic phenotype suggest potential utility of TRH and its analogues in the treatment of some neurodegenerative diseases including Parkinson's disease.
Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Citotoxinas/metabolismo , Fármacos Neuroprotectores/farmacología , Hormona Liberadora de Tirotropina , Tretinoina/farmacología , 1-Metil-4-fenilpiridinio/farmacología , Péptidos beta-Amiloides/farmacología , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Convulsivantes/farmacología , Homocisteína/farmacología , Humanos , Peróxido de Hidrógeno/farmacología , Sistema de Señalización de MAP Quinasas/fisiología , Neuroblastoma/metabolismo , Nitrocompuestos/farmacología , Oxidantes/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Propionatos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Estaurosporina/farmacología , Hormona Liberadora de Tirotropina/análogos & derivados , Hormona Liberadora de Tirotropina/farmacologíaRESUMEN
Our previous study suggests that in prenatal stress model of depression glucocorticoid receptor (GR) function in adult rats is enhanced. However, the long-term consequences of stress, a causal factor in depression, on intracellular elements involved into the regulation of GR function is poorly examined. Mitogen-activated protein kinases (MAPKs), activity of which is disturbed in depression, are important regulators of GR action, so they can mediate the effect of stress on GR function. Therefore, the aim of the present study was to investigate the levels of active phosphorylated forms of extracellular signal-regulated kinases (ERK), Jun N-terminal kinases (JNK) and the p38 kinase in the hippocampus and frontal cortex in rats subjected to prenatal stress. The concentration of MAP kinase phosphatase (MKP-1, MKP-2) and protein phosphatase-2A (PP2A), which dephosphorylate all forms of MAP kinases, were also determined. During verification of the applied model of depression, we found that prenatally stressed rats displayed high level of immobility in the Porsolt test and that the administration of imipramine, fluoxetine, mirtazapine and tianeptine for 21 days normalized this parameter. Western blot study revealed that rats subjected to prenatal stress had decreased levels of p-JNK1 and p-JNK2 in the hippocampus and p-p38 in the frontal cortex, but the concentrations of p-ERK1 and p-ERK2 were not changed. Chronic treatment with imipramine inhibited the stress-induced decrease in p-JNK1/2, while imipramine, fluoxetine and mirtazapine blocked changes in p-p38. PP2A phosphatase level was higher in the hippocampus and frontal cortex in prenatally stressed animals than in control rats. Chronic treatment with antidepressant drugs attenuated the stress-induced increase in the level of this phosphatase, but had no effect on its concentration in control animals. There was no significant difference in MKP-1 and in MKP-2 levels in both brain structures between control and prenatally stressed rats. The obtained results showed that prenatal stress decreased the levels of active form of JNK and p38, but enhanced PP2A phosphatase expression and most of these changes were reversed by antidepressant drugs. Since p-JNK and p-p38 are known to inhibit GR function their lowered levels may enhance glucocorticoid action. Furthermore, the increased PP2A concentration may intensify GR action not only by inhibition of JNK and p38 phosphorylation, but also by a direct influence on the process of GR translocation.
Asunto(s)
Depresión/fisiopatología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteína Fosfatasa 2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Proteínas Quinasas JNK Activadas por Mitógenos/efectos de los fármacos , Masculino , Fosforilación , Embarazo , Efectos Tardíos de la Exposición Prenatal , Proteína Fosfatasa 2/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Estrés Fisiológico , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacosRESUMEN
The aim of the present study was to investigate effects of some classical and new antidepressants on functional activity of the glucocorticoid receceptor (GR) induced by low corticosterone concentration in mouse fibroblast cells stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase plasmid (LMCAT cells). We found that the transcriptional activity of GR stimulated by 50 nM corticosterone was strongly attenuated by imipramine, desipramine, fluoxetine and tianeptine in a concentration-dependent way, whereas reboxetine had only a weak effect and venlafaxine was inactive. Further study revealed that the inhibitor of c-Jun N-terminal kinase - mitogen-activated protein kinase (JNK-MAPK), SP600125 (0.1 microM), reversed the imipramine-induced suppression of GR function, whereas the inhibitor of extracellular signal-regulated kinase (ERK)-MAPK, PD 98059 (15 microM), potentiated the antidepressant action. No effect of selective inhibitors of p38-MAPK, phosphatidylinositol 3-kinase (PI3-K)/Akt, and glycogen synthase kinase (GSK-3) on the imipramine-induced inhibition of GR function was detected. These data indicate that the functional activity of GR evoked by low corticosterone concentration in LMCAT cells is efficiently inhibited by tricyclic antidepressants. Moreover, it was found that JNK- and ERK-MAPK were oppositely involved in the regulation of the imipramine-induced inhibition of the GR functional activity. Thus, the present study supports the notion that the interaction of antidepressants with GR may play a role in attenuating pathological hyperactivity of HPA axis in depression.
Asunto(s)
Antidepresivos/farmacología , Receptores de Glucocorticoides/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Antidepresivos Tricíclicos/farmacología , Línea Celular Tumoral , Corticosterona/administración & dosificación , Corticosterona/farmacología , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Relación Dosis-Respuesta a Droga , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismoRESUMEN
Neurosteroids are important regulators of central nervous system function and may be involved in processes of neuronal cell survival. This study was undertaken to test the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL), pregnenolone sulfate (PGLS), and allopregnanolone (Allo) on hydrogen peroxide- and staurosporine-induced toxicity in SH-SY5Y cells. It has been found that DHEAS inhibited the hydrogen peroxide toxicity in a concentration-dependent manner, whereas DHEA was active only at higher doses. PGL and PGLS showed neuroprotective effects only at the lowest concentration. Allo had no significant effect on hydrogen peroxide-evoked lactate dehydrogenase release and at the highest concentration aggravated its toxic effects. Next part of this study evaluated neurosteroid effects on staurosporine-induced apoptosis. DHEAS, DHEA, and PGL significantly antagonized effects of staurosporine on both caspase-3 activity and mitochondrial membrane potential. PGLS and Allo inhibited the staurosporine-induced changes in both apoptotic parameters only at the lowest concentration. Antiapoptotic properties of neurosteroids were positively verified by Hoechst staining. Furthermore, as shown by calcein assay, DHEA, DHEAS, and PGL increased viability of staurosporine-treated cells, and these effects were attenuated by specific inhibitors of phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated protein kinase (ERK)-mitogen activated protein kinase (MAPK). These data indicate that neurosteroids prevent SH-SY5Y cell damage related to oxidative processes and activation of mitochondrial apoptotic pathway. Moreover, neuroprotective effects of DHEA, DHEAS seem to depend on PI3-K and ERK/MAPK signaling pathways. It can be suggested that, at physiological concentrations, all studied neurosteroids participate in the inhibition of neuronal apoptosis, but with various potencies.
Asunto(s)
Encéfalo/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Neuronas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estaurosporina/toxicidad , Esteroides/farmacología , Apoptosis/efectos de los fármacos , Encéfalo/patología , Línea Celular Tumoral , Deshidroepiandrosterona/farmacología , Sulfato de Deshidroepiandrosterona/farmacología , Inhibidores Enzimáticos/toxicidad , Humanos , L-Lactato Deshidrogenasa/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Degeneración Nerviosa/prevención & control , Neuroblastoma/metabolismo , Neuronas/patología , Oxidantes/toxicidad , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Pregnanolona/farmacología , Pregnenolona/farmacologíaRESUMEN
Antipsychotic drugs are widely used to alleviate a number of psychic disorders and have been found to modulate some immune parameters, but the molecular mechanism of their action on the proliferative activity has been poorly recognized. In the present study, we investigated effects of various antipsychotics on the proliferative activity of lymphocytes stimulated by concanavalin A (Con A) and lipopolysaccharide (LPS). Chlorpromazine (3 x 10(-6)-10(-4) M) showed the most potent effect in inhibiting 3H-thymidine incorporation into C57BL/6 mouse spleen cells stimulated by Con A and LPS. Treatment of the cells with thioridazine (10(-5)-10(-4) M), promazine (10(-5)-10(-4) M), haloperidol (10(-5)-10(-4) M), risperidone (10(-5)-10(-4) M), raclopride (3 x 10(-5) - 10(-4) M), remoxipride (3 x 10(-5)-10(-4) M) and clozapine ( 3 x 10(-5)-10(-4) M), but not with sulpiride (10(-7)-10(-4) M), suppressed proliferative activity of splenocytes after Con A stimulation. On the other hand, LPS-induced proliferation of splenocytes was inhibited by clozapine, promazine, thioridazine and haloperidol, but not by risperidone, remoxipride, sulpiride and raclopride. In the next part of the study, the influence of some kinase modulators on chlorpromazine- and clozapine-evoked inhibition of the proliferative activity of splenocytes was determined. Wortmannin, a selective phosphatidylinositol 3-kinase (PI3-K) inhibitor, blocked chlorpromazine and clozapine inhibitory effect on the mitogen-stimulated splenocyte proliferation. The involvement of PI 3-K /protein kinase B (PKB, Akt) pathway was confirmed by the results of the Western blot study, which showed that both drugs increased the level of active phospho-Ser-473 Akt, without changing the total Akt level, and decreased the level of active, nonphosphorylated glycogen synthase kinase-3 (GSK-3beta). Additionally, we have found that chlorpromazine action was also attenuated by a selective p-38-MAPK inhibitor, while clozapine effect was suppressed by a protein kinase C (PKC) activator. The obtained results indicated that atypical antipsychotic drugs markedly inhibited the proliferative activity of splenocytes only after ConA stimulation. Inhibition of the proliferative capability of splenocytes by chlorpromazine and clozapine resulted mainly from the activation of PI3-K/Akt pathway.
Asunto(s)
Antipsicóticos/farmacología , Proliferación Celular/efectos de los fármacos , Concanavalina A/farmacología , Lipopolisacáridos/farmacología , Androstadienos/farmacología , Animales , Antipsicóticos/química , Antipsicóticos/clasificación , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Clozapina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Péptidos y Proteínas de Señalización Intracelular/farmacología , Ratones , Ratones Endogámicos C57BL , Fenotiazinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Bazo/citología , Bazo/enzimología , WortmaninaRESUMEN
Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.
Asunto(s)
Trastorno Depresivo/tratamiento farmacológico , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Imipramina/administración & dosificación , Inmovilización , Metirapona/administración & dosificación , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Animales , Corticosterona/sangre , Trastorno Depresivo/sangre , Quimioterapia Combinada , Sistema Hipotálamo-Hipofisario/metabolismo , Inmovilización/métodos , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Wistar , Natación/fisiologíaRESUMEN
Topiramate, a new anticonvulsant, has been reported to possess neuroprotective effects in both in vivo and in vitro experiments. In the present study, the effect of topiramate (40 and 80 mg/kg ip) on the fully developed kainate-induced status epilepticus was evaluated in the rat. Injection of kainate (15 mg/kg ip) evoked recurrent limbic seizures which lasted several hours. Topiramate injected 1.5 h after kainate administration had no effect on the seizures and mortality of the animals. Biochemical study revealed that at 80 mg/kg ip, topiramate significantly attenuated the kainate-induced lipid peroxidation in the piriform cortex and showed similar tendency in the frontal cortex. Besides the central nervous system, the kainate-induced seizures evoked significant changes in immunoreactivity, such as reduction in thymus weight and the proliferative activity of splenocytes, and the splenocyte-increased production of interleukin-10, but not interferon-gamma. Topiramate did not affect the kainate-induced reduction in thymus weight, but attenuated changes in the proliferative activity of splenocytes. It is concluded that topiramate, when given during the fully developed kainate-induced status epilepticus in rats, has no effect on seizures, but attenuates lipid peroxidation in piriform cortex and prevents certain changes in immunoactivity.
Asunto(s)
Fructosa/análogos & derivados , Fructosa/farmacología , Peroxidación de Lípido/efectos de los fármacos , Estado Epiléptico/inmunología , Estado Epiléptico/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Ácido Kaínico/toxicidad , Peroxidación de Lípido/fisiología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/inmunología , Ratas , Ratas Wistar , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Estado Epiléptico/inducido químicamente , Estado Epiléptico/fisiopatología , Timo/efectos de los fármacos , Timo/inmunología , Timo/metabolismo , TopiramatoRESUMEN
Antipsychotic drugs can modulate transcription factors and also nuclear receptors, but their action on glucocorticoid receptors (GR)-members of the steroid/thyroid hormone receptor family has not been studied so far. In the present study we investigated effects of various antipsychotics on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with a mouse mammary tumor virus promoter (LMCAT cells). Chlorpromazine (3-100 microM) inhibited the corticosterone-induced gene transcription in a concentration- and time-dependent manner. Clozapine showed a similar, but less potent effect, while haloperidol acted only in high concentrations, and other antipsychotic drugs (sulpiride, raclopride, remoxipride) were without any effect. It was also found that a phorbol ester (an activator of protein kinase C (PKC)) and A-23187 (Ca(2+)-ionophore) attenuated the inhibitory effect of chlorpromazine on the GR-induced gene transcription. An antagonist of the L-type Ca(2+) channel, as well as an inhibitor of phospholipase C (PLC) inhibited the corticosterone-induced gene transcription, but had no effect on the chlorpromazine-induced changes. The involvement of a PKC/PLC pathway in the chlorpromazine action was confirmed by Western blot analysis which showed that the drug in question decreased the PLC-beta(1) protein level, and to a lesser extent that of the PKC-alpha protein in LMCAT cells. The aforementioned data suggest that inhibition of the glucocorticosteroid-induced gene transcription by chlorpromazine and clozapine may be a mechanism by which these drugs block some effects induced by glucocorticoids. The inhibitory effect of chlorpromazine on the corticosterone-induced gene transcription seems to depend on the inhibition of Ca(2+) influx and/or the inhibition of some calcium-dependent enzymes, e.g. phospholipase beta(1).
Asunto(s)
Antipsicóticos/farmacología , Calcio/farmacología , Clorpromazina/farmacología , AMP Cíclico/análogos & derivados , Receptores de Glucocorticoides/fisiología , Acetato de Tetradecanoilforbol/análogos & derivados , Transcripción Genética/efectos de los fármacos , Animales , Calcimicina/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Línea Celular , Línea Celular Transformada , Cloranfenicol O-Acetiltransferasa/efectos de los fármacos , Cloranfenicol O-Acetiltransferasa/genética , Cloranfenicol O-Acetiltransferasa/metabolismo , Clozapina/farmacología , Colforsina/farmacología , AMP Cíclico/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Estrenos/farmacología , Fibroblastos , Regulación de la Expresión Génica , Genes Reporteros/efectos de los fármacos , Genes Reporteros/fisiología , Haloperidol/farmacología , Histamina/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Ionóforos/farmacología , Virus del Tumor Mamario del Ratón , Ratones , Nifedipino/farmacología , Ésteres del Forbol/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Proteína Quinasa C/efectos de los fármacos , Proteína Quinasa C/metabolismo , Proteína Quinasa C-alfa , Pirilamina/farmacología , Pirrolidinonas/farmacología , Racloprida/farmacología , Receptores de Glucocorticoides/efectos de los fármacos , Remoxiprida/farmacología , Sulfonamidas/farmacología , Sulpirida/farmacología , Acetato de Tetradecanoilforbol/farmacología , Tionucleótidos/farmacología , Fosfolipasas de Tipo C/efectos de los fármacos , Fosfolipasas de Tipo C/metabolismoRESUMEN
Recent studies indicate a role of the immune system in the behavioral effects of amphetamine in rodents. In the present study we attempted to find a connection between the behavioral changes induced by repeated, intermittent administration of amphetamine and some immunological consequences of sensitization to amphetamine in mice. Male Albino Swiss mice were treated repeatedly (for 5 days) with amphetamine (1 mg/kg, i.p.). On day 9, they received a challenge dose of amphetamine (1 mg/kg). Acute administration of amphetamine increased their locomotor activity by ca. 40%. In animals treated repeatedly with amphetamine, the challenge dose of the psychostimulant induced behavioral sensitization, i.e. the higher locomotor activation as compared with that after its first administration to mice. Immune functions were evaluated by the ability of splenocytes to proliferate and to produce cytokines such as interferon gamma (IFN-gamma), interleukin (IL)-4 and IL-10. Acute amphetamine administration significantly decreased, by ca. 30% and 25%, the proliferation of splenocytes in response to an optimal and a suboptimal dose of concanavalin A (Con A), respectively, and increased their ability to produce IL-4. Chronic intermittent treatment with amphetamine significantly decreased, by ca. 65% and 50%, the proliferative response of T cells to an optimal and a suboptimal dose of Con A, respectively, and diminished by 20% the metabolic activity of splenocytes. The above data showed that both acute and chronic amphetamine administration diminished some aspects of the cell-mediated immunity; nevertheless, immunosuppression was particularly evident in amphetamine-sensitized mice. Our findings seem to indicate possible importance of monitoring and correcting immune changes in the therapy of amphetamine addiction.
Asunto(s)
Anfetamina/inmunología , Sistema Inmunológico/fisiología , Inmunización , Animales , Conducta Animal/fisiología , División Celular/fisiología , Linfocitos/metabolismo , Linfocinas/biosíntesis , Masculino , Ratones , Tamaño de los Órganos , Bazo/anatomía & histología , Bazo/citología , Bazo/metabolismo , Timo/anatomía & histologíaRESUMEN
BACKGROUND: Depression is associated with activation of the inflammatory response system (IRS). In humans, antidepressants significantly increase the production of interleukin-10 (IL-10), a negative immunoregulatory cytokine. The aims of the present study were to examine the effects of desipramine, a tricyclic antidepressant, on the IRS in C57BL/6 mice with and without exposure to chronic mild stress (CMS). METHODS: We examined the effects of desipramine on the cytotoxic activity of natural killer (NK) cells, the proliferative responses of lymphocytes after stimulation with IL-1, IL-2, lipopolysaccharide (LPS), concanavaline-A (Con-A), phytohaemagglutinin-P (PHA), pokeweed mitogen (PWM), and anti-CD3 monoclonal antibodies, the production of IL-2, IL-4, IL-10 and interferon-gamma (IFNgamma) by T lymphocytes and the ability of B cells to proliferate after stimulation by lipopolysaccharide (LPS). RESULTS: Prolonged treatment of C57BL/6 mice subjected to CMS with desipramine increases the ability of T cells to produce IL-10 and the ability of B cells to proliferate after stimulation with LPS; and significantly decreases the cytotoxic activity of NK cells and the proliferative responses of lymphocytes after stimulation with Con-A, PHA and anti-CD3 monoclonal antibodies. Repeated administration of desipramine to non-stressed mice increases the activity of T lymphocytes, lowers that of B lymphocytes, increases the production of IL-10 by T cells and has no significant effect on the activity of NK cells. CONCLUSION: Prolonged desipramine treatment of stressed and non-stressed C57BL/6 mice induces an increase in the production of IL-10, an anti-inflammatory cytokine.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Trastorno Depresivo/tratamiento farmacológico , Desipramina/farmacología , Estrés Psicológico , Animales , Antidepresivos Tricíclicos/efectos adversos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Trastorno Depresivo/inmunología , Desipramina/efectos adversos , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Antidepressant drugs have been shown to reverse some changes evoked by glucocorticoids or stress. In the present study we attempted to find out whether imipramine, one of the most frequently used antidepressant drugs, interfered with glucocorticoids, modulating the production of IFN-gamma and IL-10, pro-inflammatory and anti-inflammatory cytokines, respectively. We observed a significant inhibitory effect of hydrocortisone, dexamethasone and the glucocorticoid receptor agonist RU 28362, used at doses of 10(-6) and 10(-5) M, on the production of IFN-gamma and IL-10 by whole blood cells stimulated by mitogens. Imipramine at doses of 10(-6) and 10(-5) M did not modulate IFN-gamma or IL-10 production, whereas at a dose of 10(-5) M it increased the production of IL- 10 and decreased that of IFN-gamma, those results being statistically insignificant, though. A combination of imipramine and dexamethasone or hydrocortisone at doses of 10(-6) or 10(-5) M significantly suppressed the production of IFN-gamma and IL-10, the level of inhibition being similar to that observed for glucocorticoids alone. The classic antidepressant imipramine was not able to modulate the suppressive effect of "stress" doses of hydrocortisone on the production of cytokines.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Glucocorticoides/farmacología , Imipramina/farmacología , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Mitógenos/farmacología , Adulto , Androstanoles/farmacología , Dexametasona/farmacología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hidrocortisona/farmacología , Técnicas In Vitro , Interferón gamma/sangre , Interleucina-10/sangre , Masculino , Receptores de Glucocorticoides/agonistasRESUMEN
The effect of physiological and pharmacologically induced thymus involution was studied in 12-week-old female C57BL mice. Thymus involution was estimated by measurement of the thymus weight and the ability of thymocytes to induce a graft-versus-host (GvH) reaction at 48 h after delivery or drug administration in comparison with control (virgin, saline-treated) mice. The thymus weight and immunoreactivity of thymocytes after delivery were reduced in a statistically significant manner by ca. 80 and 75%, respectively. On the other hand, hydrocortisone administration decreased the thymus weight (by ca. 60%), but did not change the ability of thymocytes to induce a GvH reaction. Cyclophosphamide administration significantly reduced both the thymus weight and the reactivity of thymocytes. The present study suggests that the transient thymus involution observed after delivery, connected with a loss of the ability of thymocytes to induce a GvH reaction, cannot be explained merely by elimination of a steroid-sensitive cortical cell population, since the GvH reactivity of thymocytes was preserved in hydrocortisone-treated mice.
Asunto(s)
Inmunocompetencia/inmunología , Linfocitos T/inmunología , Timo/inmunología , Animales , Animales Recién Nacidos , Antiinflamatorios/farmacología , Peso Corporal/efectos de los fármacos , Ciclofosfamida/farmacología , Femenino , Reacción Injerto-Huésped/efectos de los fármacos , Reacción Injerto-Huésped/inmunología , Hidrocortisona/farmacología , Inmunocompetencia/efectos de los fármacos , Inmunosupresores/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Tamaño de los Órganos/efectos de los fármacos , Periodo Posparto/inmunología , Embarazo , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/trasplante , Timo/citología , Timo/efectos de los fármacosRESUMEN
The effects of desipramine and fluoxetine on the swelling of hind paws, radiologically-detectable bone destruction of hind paws, increase in spleen and popliteal lymph node weight, increase in metabolic activity of splenocytes and increase in proliferative activity of splenocytes and popliteal lymph node cells from right adjuvant injected paw in male C57BL/6 mice were studied on the 17th day after induction of post-adjuvant arthritis. Drugs were administered once-daily ip at a dose of 10 mg/kg. Fourteen days of desipramine administration, starting on the third day after injection of the adjuvant, significantly increased edema and radiologically assessed bone destruction, spleen and popliteal lymph node weight whereas fluoxetine induced an opposite effect, but it did not reduce edema in comparison with saline-treated control. Two-week desipramine administration significantly increased metabolic activity of splenocytes and proliferative activity of popliteal lymph node cells from the right adjuvant-injected paw, whereas 14 days of fluoxetine injection reduced proliferative activity of splenocytes in comparison with the saline-treated mice. Desipramine administration 30 days before and 17 days after adjuvant injection did not change these parameters in spite of reduction of proliferative activity of splenocytes. These findings indicate that: 1) fluoxetine has a suppressive effect on some of the local and systemic changes which occur in adjuvant-induced arthritis in mice, 2) two-week desipramine administration significantly increases whereas 47-day desipramine treatment does not change most of local and systemic parameters of post-adjuvant disease in C57BL/6 mice, 3) the action of fluoxetine differs from that of desipramine in this model of autoimmunodisease probably as a result of the distinct effect of these two drugs on corticoids levels and on the activity of a sympathetic nervous system.
Asunto(s)
Antidepresivos de Segunda Generación/uso terapéutico , Antidepresivos Tricíclicos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Desipramina/uso terapéutico , Fluoxetina/uso terapéutico , Animales , Huesos/efectos de los fármacos , Edema/tratamiento farmacológico , Inyecciones Intraperitoneales , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/efectos de los fármacos , Bazo/metabolismoRESUMEN
The purpose of the present study was to investigate whether multiparity in women prevents some age-related changes in their cell function, as is known for age and sex. 49 women from the same village, free of acute inflammation or neoplastic diseases, were selected and divided into the following three groups: nulliparous 1935 years old, nulliparous 65 92 years old and multiparous (3-9 pregnancies) 65-88 years old. The response of their blood-lymphocytes to phytohaemagglutinin-P was estimated by thymidine uptake, number of mitoses and number of sister-chromatid exchanges. The stimulation index, mitotic index and proliferative rate in the aging nulliparous women were significantly lower than in the younger nulliparous women, but the latter group (young nulliparous) did not differ in their lymphocyte parameters assayed, from the values in the aging multiparous women breast-feeding their newborn. It is concluded that when the proliferative capacity to mitogen in elderly multiparous women (after 3-9 pregnancies) is related to breast feeding, it is similar to the proliferative capacity in young women. We suggest therefore, that breast feeding is beneficial not only to the newborns, but also to their mothers.
Asunto(s)
Activación de Linfocitos/inmunología , Mitógenos/farmacología , Paridad/inmunología , Fitohemaglutininas/farmacología , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/inmunología , Células Cultivadas , Femenino , Humanos , Activación de Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Persona de Mediana Edad , Linfocitos T/efectos de los fármacosRESUMEN
Immunomodulation of cell-mediated immunity is demonstrated in mice, after administration of desipramine, a noradrenaline-reuptake inhibitor, with or without exposing the mice later to an acute swimming stress. A single i.p. injection of 10 mg/kg desipramine to naive mice increased the relative weight of their spleens, the response of their splenocytes to the mitogen concavaline-A and their ability to produce IL-10, as compared to saline controls. Exposing the desipramine-treated mice to a swimming stress significantly reduced these parameters, as well as the levels of IL-2 and IFN-gamma, as compared to desipramine-treated mice. Stress alone reduced the weight of the spleen, and the ability of splenocytes to produce IFN-gamma. As desipramine and acute stress have stimulatory effect on the sympathetic system, it is suggested that a concomitant administration of the drug and a stressful event of these mice, change the splenocytes' micro-environment of sympathetic transmitters, and inhibit their function. These results may be partially due to impairment in the T-helper cell function by a beta-adrenoreceptor-dependent mechanism.