RESUMEN

This study was designed to investigate the protective effect of melatonin in a preclinical animal model of mania induced by ouabain (OUA). Male Wistar rats were pretreated with melatonin (5 or 20mg/kg; intraperitoneal, i.p.) for seven days or with the mood stabilizer lithium chloride (positive control) (45 mg/kg, per oral, p.o.). One day after the last dose, animals received an intracerebroventricular (i.c.v.) injection of OUA (5µl, 10(-5)M), a Na(+)K(+)ATPase-inhibiting compound. Locomotor activity was assessed in the open-field test (OFT). The levels of reactive species (RS), protein carbonyl (PC) and non-protein thiols (NPSH), as well as the activities of the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured in the cerebral cortex and hippocampus of rats. OUA markedly increased the locomotor activity in the OFT, and the pretreatment with melatonin or lithium chloride prevented this effect. Melatonin treatment (similar to lithium) was also effective in preventing the following alterations elicited by OUA: increase of RS and PC levels; depletion of NPSH levels; increase of SOD activity; and inhibition of CAT and GPx activities. Moreover, we found that brain oxidative stress and behavioural alterations elicited by OUA were significantly correlated. Our study showed that Melatonin, similarly to lithium, protected against OUA-induced brain oxidative stress and hyperlocomotion in rats. Thus, our findings reinforce the notion that oxidative stress may play an important role in the manic-like behavioural. Therefore, we indicate that melatonin has antimanic-like action, suggesting a potential role for this substance in the pharmacological management of Bipolar disorder.

Asunto(s)

Trastorno Bipolar/tratamiento farmacológico , Locomoción/efectos de los fármacos , Melatonina/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antimaníacos/farmacología , Trastorno Bipolar/inducido químicamente , Trastorno Bipolar/metabolismo , Trastorno Bipolar/psicología , Catalasa/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Cloruro de Litio/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Ouabaína , Carbonilación Proteica , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo

RESUMEN

OBJECTIVES: The excitotoxin 3-nitropropionic acid (3-NP) induces a suitable experimental model of Huntington's disease (HD). This compound induces neurodegeneration via glutamatergic activation and oxidative stress, suggesting that the metabotropic glutamate receptor blockage and free radical scavenging are potential therapeutic targets in HD. In this study, we evaluated the role of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP), a selective mGlu5 receptor antagonist, in a 3-NP model of HD. METHODS: We administered 3-NP (20 mg/kg, intraperitoneal) to rats for 4 days. MTEP at doses of 2·5 and 5 mg/kg was administered 30 min before 3-NP. Behavioral tests and biochemical experiments were performed to assess the effects of 3-NP and the ability of MTEP to ameliorate these changes. RESULTS: 3-NP administration induced body weight loss, decreased locomotor activity, and inhibition of succinate dehydrogenase and Na(+)-K(+) adenosine triphosphate (ATP)ase activities in rat striatum. We also observed increases in reactive species (RS) levels and glutathione reductase activity, decreased non-protein thiol levels, and an inhibition of glutathione peroxidase activity in the striatum of rats treated with 3-NP. Notably, all of these effects were attenuated by MTEP treatment. DISCUSSION: Our results demonstrate the neuroprotective effect of MTEP and reinforce the involvement of mGluR5 in 3-NP-induced oxidative stress in rat striatum.

Asunto(s)

Cuerpo Estriado/efectos de los fármacos , Enfermedad de Huntington/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Enfermedad de Huntington/fisiopatología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Nitrocompuestos , Estrés Oxidativo/fisiología , Propionatos , Ratas Wistar , Receptor del Glutamato Metabotropico 5/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Succinato Deshidrogenasa/metabolismo , Pérdida de Peso/efectos de los fármacos , Pérdida de Peso/fisiología

RESUMEN

Information on the effect of an intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) on noncognitive behaviour in rodents such as depression states is scarce. Thus, the aim of this study was to examine the depressive-like effect of STZ injected by the i.c.v. route in mice and the potential protective effect of fluoxetine, antitumour necrosis factor-α (anti-TNF-α) and thalidomide. Our results indicated that a single injection of STZ (0.1 mg/site) promoted depressive-like behaviour in the tail suspension and sucrose preference tests without altering either locomotor activity or plasma glucose levels. We also showed that STZ increased TNF-α levels in the hippocampus of mice. Fluoxetine (32 mg/kg, intraperitoneally. 30 min before STZ injection), and the anti-TNF-α antibody (0.1 pg/site, i.c.v.) and thalidomide (3 mg/kg, subcutaneously), coadministered with STZ, prevented these effects. This is the first study to report depressive-like effects of STZ using the i.c.v. route in mice. We concluded that fluoxetine, anti-TNF-α antibody and thalidomide were effective in preventing depressive-like behaviour and the increase in TNF-α levels in the hippocampus of mice induced by an i.c.v. injection of STZ, reinforcing the involvement of TNF-α in the pathophysiology of depression. This model and the mechanisms studied may contribute towards the development of new antidepressant drugs and enhance the options for studying depression.

Asunto(s)

Antidepresivos/uso terapéutico , Depresión/prevención & control , Modelos Animales de Enfermedad , Fluoxetina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Talidomida/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/uso terapéutico , Antidepresivos/administración & dosificación , Conducta Animal/efectos de los fármacos , Depresión/inducido químicamente , Depresión/inmunología , Depresión/metabolismo , Sacarosa en la Dieta/administración & dosificación , Preferencias Alimentarias/efectos de los fármacos , Suspensión Trasera , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Hipocampo/metabolismo , Inmunosupresores/uso terapéutico , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Estreptozocina , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

This study was designed to investigate the potential neuroprotective effect of exercise in a mouse model of Alzheimer's disease (AD) induced by intracerebroventricular (i.c.v.) injection of beta-amyloid1₋40 (Aß1₋40) peptide. For this aim, male Swiss Albino mice were submitted to swimming training (ST) with progressive increase in intensity and duration for 8 weeks before Aß1₋40 administration (400 pmol/animal; 3 µl/site, i.c.v. route). The cognitive behavioral, oxidative stress, and neuroinflammatory markers in hippocampus and prefrontal cortex of mice were assessed 7 days after Aß1₋40 administration. Our results demonstrated that ST was effective in preventing impairment in short- and long-term memories in the object recognition test. ST attenuated the increased levels of reactive species and decreased non-protein thiol levels in hippocampus and prefrontal cortex induced by Aß1₋40. Also, Aß1₋40 inhibited superoxide dismutase activity and increased glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities in hippocampus and prefrontal cortex-alterations that were mitigated by ST. In addition, ST was effective against the increase of tumor necrosis factor-alpha and interleukin-1 beta levels and the decrease of interleukin-10 levels in hippocampus and prefrontal cortex. This study confirmed the hypothesis that exercise is able to protect against some mechanisms of Aß1₋40-induced neurotoxicity. In conclusion, we suggest that exercise can prevent the cognitive decline, oxidative stress, and neuroinflammation induced by Aß1₋40 in mice supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of AD.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/toxicidad , Modelos Animales de Enfermedad , Fragmentos de Péptidos/toxicidad , Condicionamiento Físico Animal/fisiología , Enfermedad de Alzheimer/inducido químicamente , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Ratones , Condicionamiento Físico Animal/métodos , Músculo Cuádriceps/efectos de los fármacos , Músculo Cuádriceps/metabolismo , Distribución Aleatoria

RESUMEN

The present study investigated a possible antidepressant-like activity of hesperidin using two predictive tests for antidepressant effect in mice: the forced swimming test (FST) and the tail suspension test (TST). Results demonstrated that hesperidin (0.1, 0.3 and 1 mg/kg, intraperitoneal, i.p.) decreased the immobility time in the FST and TST without affecting the locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) on the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (pCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) and WAY100635 (0.1 mg/kg, subcutaneous, s.c., a selective 5-HT(1A) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a ß-adrenoceptor antagonist), AMPT (100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or MDL72222 (1 mg/kg, i.p., a 5-HT(3) receptor antagonist) did not block the antidepressant-like effect of hesperidin (0.3 mg/kg, i.p.) in the TST. Administration of hesperidin (0.01 mg/kg, i.p.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. The antidepressant-like effect caused by hesperidin in mice in the TST was dependent on an interaction with the serotonergic 5-HT(1A) receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like property and may be of interest source for therapeutic agent for the treatment of depressive disorders.

Asunto(s)

Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Hesperidina/uso terapéutico , Receptor de Serotonina 5-HT1A/metabolismo , Animales , Antidepresivos/farmacología , Depresión/metabolismo , Conducta Exploratoria/efectos de los fármacos , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Hesperidina/farmacología , Suspensión Trasera , Pérdida de Tono Postural/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Prazosina/farmacología , Prazosina/uso terapéutico

RESUMEN

The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced swimming test. Our results demonstrate that hesperidin (0.1, 0.3 and 1 mg/kg; intraperitoneal) decreased the immobility time in the forced swimming test without affecting locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) in the forced swimming test was prevented by pretreating mice with naloxone (1 mg/kg, a nonselective opioid receptor antagonist) and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl] acetamide (DIPPA (1 mg/kg), a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, a peripherally acting opioid receptor antagonist), naltrindole (3 mg/kg, a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, a selective µ-opioid receptor antagonist) or caffeine (3 mg/kg, a nonselective adenosine receptor antagonist). In addition, a sub-effective dose of hesperidin (0.01 mg/kg) produced a synergistic antidepressant-like effect in the forced swimming test when combined with a sub-effective dose of morphine (1 mg/kg). The antidepressant-like effect of hesperidin in the forced swimming test on mice was dependent on its interaction with the κ-opioid receptor, but not with the δ-opioid, µ-opioid or adenosinergic receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.

Asunto(s)

Antidepresivos/farmacología , Hesperidina/farmacología , Receptores Opioides kappa/metabolismo , Natación , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratones , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Purinérgicos P1/metabolismo

RESUMEN

CyberMed is a free framework (GPL license) for the development of medical applications for simulation based on virtual reality. The framework allows to decrease development time and offers complete synchronization among several functionalities that can be selected by the programmer, as stereoscopic visualization, haptics and deformation, among others. An important feature of this framework is an online evaluation module that allows the classification of the user performance according to several simulation and interaction data. CyberMed can be used by programmers of any expertise level and offers high-level access for non-experts and low-level access for expert programmers. The low-level access allows the inclusion or extension of the framework functionalities.

Asunto(s)

Simulación por Computador , Educación Médica/métodos , Interfaz Usuario-Computador , Estudios de Evaluación como Asunto , Internet