RESUMEN
The aim of this study is to investigate the effect of metyrosine on ischemia-reperfusion (I/R) induced ovarian injury in rats in terms of biochemistry and histopathology. Rats were divided into: ovarian I/R (OIR), ovarian I/R+50 mg/kg metyrosine (OIRM) and sham (SG) operations. OIRM group received 50 mg/kg metyrosine one hour before the application of the anesthetic agent, OIR and SG group rats received equal amount of distilled water to be used as a solvent orally through cannula. Following the application of the anesthetic agent, ovaries of OIRM and OIR group rats were subjected to ischemia and reperfusion, each of which took two hours. This biochemical experiment findings revealed high levels of malondialdehyde (MDA) and cyclo-oxygenase-2 (COX-2) and low levels of total glutathione (tGSH), superoxide dismutase (SOD) and cyclo-oxygenase-1 (COX-1) in the ovarian tissue of OIR group, with significant histopathological injury. In metyrosine group, MDA and COX-2 levels were lower than the OIR group whereas tGSH, SOD and COX-1 levels were higher, with slighter histopathological injury. Our experimental findings indicate that metyrosine inhibits oxidative and pro-inflammatory damage associated with ovarian I/R in rats. These findings suggest that metyrosine could be useful in the treatment of ovarian injury associated with I/R.
Asunto(s)
Ovario , Daño por Reperfusión , Femenino , Ratas , Animales , Ovario/metabolismo , alfa-Metiltirosina/metabolismo , alfa-Metiltirosina/farmacología , Ratas Wistar , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/farmacología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Isquemia/metabolismo , Isquemia/patología , Glutatión , Reperfusión , Superóxido Dismutasa/metabolismo , Estrés OxidativoRESUMEN
The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, ß adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.
Asunto(s)
Agonistas Adrenérgicos/farmacología , Antagonistas Adrenérgicos/farmacología , Amantadina/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Amantadina/administración & dosificación , Animales , Antidepresivos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Masculino , Ratones , Neurogénesis/efectos de los fármacos , alfa-Metiltirosina/farmacologíaRESUMEN
The dopaminergic system of zebrafish is complex and the numerous pathways and receptors in the central nervous system (CNS) are being extensively studied. A critical factor for the synthesis, activation and release of catecholamines (CAs) is the presence of tyrosine hydroxylase, an enzyme which converts L-tyrosine into levodopa. Levodopa thus is the intermediary in the synthesis of dopamine (DA) and norepinephrine (NE) and promotes its release; therefore, CAs play an important role in the CNS with hormonal functions. Here, we use levodopa/carbidopa to clarify the involvement of the dopaminergic pathway in the stress response in zebrafish submitted to an acute stress challenge. Acute stress was induced by chasing fish with a net for 2 min and assessed by measuring whole-body cortisol levels. Two experiments were carried out, the first with exposure to levodopa/carbidopa and the second with exposure to AMPT and levodopa/carbidopa. Levodopa/carbidopa balances the stress response through its action on the zebrafish hypothalamic-pituitary-adrenal (HPA) axis. Changes in cortisol levels suggest that DA was related to the balance of the stress response and that NE decreased this response. These effects were specific to stress since levodopa/carbidopa did not induce changes in cortisol in non-stressed fish.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Carbidopa/farmacología , Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Levodopa/farmacología , Estrés Fisiológico , Pez Cebra/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Neuronas Dopaminérgicas/metabolismo , Combinación de Medicamentos , Inhibidores Enzimáticos/farmacología , Femenino , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Pez Cebra/antagonistas & inhibidores , Proteínas de Pez Cebra/metabolismo , alfa-Metiltirosina/farmacologíaRESUMEN
Dopaminergic neurons have the ability to release Dopamine from their axons as well as from their soma and dendrites. This somatodendritically-released Dopamine induces an autoinhibition of Dopaminergic neurons mediated by D2 autoreceptors, and the stimulation of neighbor GABAergic neurons mediated by D1 receptors (D1r). Here, our results suggest that the somatodendritic release of Dopamine in the substantia nigra (SN) may stimulate GABAergic neurons that project their axons into the hippocampus. Using semiquantitative multiplex RT-PCR we show that chronic blockade of the Dopaminergic neurotransmission with both AMPT and reserpine specifically decreases the expression levels of D1r, remarkably this may be the result of an antagonistic effect between AMPT and reserpine, as they induced the expression of a different set of genes when treated by separate. Furthermore, using anterograde and retrograde tracing techniques, we found that the GABAergic neurons that express D1r also project their axons in to the CA1 region of the hippocampus. Finally, we also found that the same treatment that decreases the expression levels of D1r in SN, also induces an impairment in the performance in an appetitive learning task that requires the coding of reward as well as navigational skills. Overall, our findings show the presence of a GABAergic interconnection between the SNr and the hippocampus mediated by D1r.
Asunto(s)
Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Receptores de Dopamina D1/biosíntesis , Reserpina/farmacología , Sustancia Negra/metabolismo , alfa-Metiltirosina/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Animales , Antagonistas de los Receptores de Dopamina D2/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/biosíntesis , Neuronas Dopaminérgicas/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Expresión Génica , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos BALB C , Fenotipo , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/biosíntesis , Receptores de Dopamina D2/genética , Sustancia Negra/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Our study sought to evaluate the anxiolytic and antidepressant activities of oleanolic acid as well as the neural mechanisms involved. Animal models such as barbiturate sleep-induction, light-dark box, elevated plus maze, forced swimming test, tail suspension test and open field test were conducted. Male Albino Swiss mice were treated orally with vehicle 10 mL/kg, fluoxetine 20 mg/kg, imipramine 15 mg/kg, diazepam 1 mg/kg or oleanolic acid 5-40 mg/kg. Pretreatment (intraperitoneal) of animals with pentylenetetrazole (PTZ) 20 mg/kg, 1-(2-methoxyphenyl)-4-[4- (2-phthalimido) butyl]piperazine hydrobromide (NAN-190) 0.5 mg/kg, p-chlorophenylalanine methyl ester (PCPA) 100 mg/kg or α-methyl-p-tyrosine (AMPT) 100 mg/kg, WAY100635 (WAY) 0.3 mg/kg, prazosin (PRAZ) 1 mg/kg, yohimbine 2 mg/kg as well as monoamine oxidase assay and hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Oleanolic acid potentiated the hypnotic effect of barbiturate and demonstrated an anxiolytic effect in both the light-dark box and elevated plus maze. This effect was not reversed by PTZ. Acute and/or chronic oral treatment of mice with oleanolic acid (5-20 mg/kg) elicited an antidepressant effect in the forced swimming test and the tail suspension test without interfering with the locomotor activity. The antidepressant effect of oleanolic acid was attenuated by NAN-190, AMPT, PCPA, WAY and PRAZ. Although monoamine oxidase activity remained unaltered by oleanolic acid, chronic administration of oleanolic acid augmented hippocampal BDNF level. These findings demonstrate multiple mechanisms of the anxiolytic and antidepressant effect of oleanolic acid.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Ácido Oleanólico/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Diazepam/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fenclonina/análogos & derivados , Fenclonina/farmacología , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Imipramina/farmacología , Masculino , Ratones , Monoaminooxidasa/metabolismo , Actividad Motora/efectos de los fármacos , Ácido Oleanólico/antagonistas & inhibidores , Pentilenotetrazol/farmacología , Piperazinas/farmacología , Piridinas/farmacología , alfa-Metiltirosina/farmacologíaRESUMEN
The nigrostriatal pathway is very likely involved in sleep regulation, considering the occurrence and high prevalence of sleep-related disorders in patients with Parkinson's disease. Indeed, dopaminergic neurons in the ventral tegmental area were recently shown to fire in bursts during paradoxical sleep (PS), but little is known about the activity of the nigrostriatal dopamine (DA) cells in relation to PS. In view of that we hypothesized that paradoxical sleep deprivation (PSD) may play a relevant role in nigrostriatal tyrosine hydroxylase (TH) expression and, subsequently, in sleep rebound. The present study was designed to determine the effects of PSD in the nigrostriatal pathway in mice by means of neurochemical and behavioral approaches. Intraperitoneal reserpine (1 mg/kg) associated to α-methyl-p-tyrosine (αMT) (250 mg/kg) to produce catecholamine depletion, or rotenone (10 mg/kg) to increase striatal DA turnover were injected 30 min before the 24 h of PSD. Catalepsy and open-field tests indicated that motor deficits induced by reserpine-αMT were counteracted by PSD, which, in contrast, potentiated the motor impairment induced by rotenone. Besides, PSD produced down-regulation on TH expression within the substantia nigra pars compacta and striatum, without affecting the number or the optical density of dopaminergic neurons present in the respective areas. Interestingly, PSD potentiated the downregulation of TH expression in the substantia nigra pars compacta and striatum induced by the co-administration of reserpine-αMT. These results reinforce the notion of a strong participation of DA in PS, as a consequence of the modulation of TH protein expression in the nigrostriatal pathway.
Asunto(s)
Neuronas Dopaminérgicas/enzimología , Actividad Motora , Sueño REM/fisiología , Sustancia Negra/enzimología , Tirosina 3-Monooxigenasa/metabolismo , Animales , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/citología , Regulación hacia Abajo , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/enzimología , Reserpina/farmacología , Privación de Sueño/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , alfa-Metiltirosina/farmacologíaRESUMEN
The aim of this study was to investigate the involvement of noradrenaline, serotonin, and subtypes of glutamate receptors in the antidepressant-like effects of N-acetylcysteine (NAC). The tail suspension test was used with male CF1 albino mice. D,L-α-methyl-ρ-tyrosine and ρ-chlorophenylalanine methyl ester hydrochloride were used as synthesis inhibitors of noradrenaline and serotonin, respectively. N-methyl-D-aspartate (NMDA) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione were used as an NMDA receptor agonist and an α-amino acid-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptor antagonist, respectively. NAC (10, 25, and 50 mg/kg intraperitoneally) significantly (P<0.05) decreased tail suspension test immobility time, whereas pretreatment with D,L-α-methyl-ρ-tyrosine, ρ-chlorophenylalanine methyl ester hydrochloride, and NMDA partially prevented (P<0.05) the effects of NAC (25 mg/kg), and pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione completely abolished (P<0.01) this effect. The study corroborates the antidepressant-like effects of NAC in the TST, a model with a well-established predictive value. The results point to the key role of AMPA receptors in the mechanism of the antidepressant-like action of NAC. Like other AMPA potentiators, NAC indirectly modulates noradrenaline and serotonin pathways. It is suggested that the value of NAC as an antidepressant arises from combined and intertwined effects on a variety of pathways.
Asunto(s)
Acetilcisteína/farmacología , Antidepresivos/farmacología , Suspensión Trasera/fisiología , Receptores AMPA/agonistas , Acetilcisteína/antagonistas & inhibidores , Animales , Antidepresivos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Inhibidores Enzimáticos/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Fenclonina/análogos & derivados , Fenclonina/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , N-Metilaspartato/farmacología , Quinoxalinas/farmacología , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/fisiología , alfa-Metiltirosina/farmacologíaRESUMEN
We have recently shown that the hexanic extract from leaves of Schinus molle produces antidepressant-like effects in the tail suspension test in mice. This study investigated the antidepressant-like effect of the ethanolic extract from aerial part of S. molle in the forced swimming test and tail suspension test in mice, two predictive models of depression. Moreover, we investigated the antidepressant potential of rutin, a flavonoid isolated from the ethanolic extract of this plant and the influence of the pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester (PCPA) and alpha-methyl-p-tyrosine (AMPT), respectively in the antidepressant-like effect of this flavonoid. The administration of the ethanolic extract produced a reduction in the immobility time in the tail suspension test (dose range 600-1000 mg/kg, p.o.), but not in the forced swimming test. It also produced a reduction in the ambulation in the open-field test in mice not previously habituated to the arena, but no effect in the locomotor activity in mice previously habituated to the open-field. The administration of rutin reduced the immobility time in the tail suspension test (0.3-3 mg/kg, p.o.), but not in the forced swimming test, without producing alteration in the locomotor activity. In addition, pretreatment of mice with PCPA (100 mg/kg, i.p., for 4 consecutive days) or AMPT (100 mg/kg, i.p.) prevented the anti-immobility effect of rutin (0.3 mg/kg, p.o.) in the tail suspension test. The results firstly indicated the antidepressant-like effect of the ethanolic extract of S. molle in the tail suspension test may be dependent on the presence of rutin that likely exerts its antidepressant-like effect by increasing the availability of serotonin and noradrenaline in the synaptic cleft.
Asunto(s)
Anacardiaceae/química , Antidepresivos , Epinefrina/fisiología , Rutina/farmacología , Serotonina/fisiología , Animales , Dopamina/biosíntesis , Inhibidores Enzimáticos/farmacología , Epinefrina/biosíntesis , Etanol , Fenclonina/farmacología , Suspensión Trasera/psicología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Extractos Vegetales/farmacología , Rutina/aislamiento & purificación , Serotonina/biosíntesis , Solventes , Natación/psicología , alfa-Metiltirosina/farmacologíaRESUMEN
Lamotrigine is an anticonvulsant drug that is also effective in the treatment of mood disorders, especially bipolar disorder. However, few studies have been conducted in animal models of depression to evaluate its mechanism of action. The present study investigated the effect of lamotrigine in the forced swimming test in mice and the involvement of the noradrenergic system in this effect. Lamotrigine (20-30 mg/kg, i.p.) decreased the immobility time in the forced swimming test and the number of crossings in the open-field test. In addition, the pretreatment of mice with the inhibitor of the enzyme tyrosine hydroxylase, alpha-methyl-p-tyrosine (100 or 250 mg/kg), prevented the antidepressant-like effect of lamotrigine (30 mg/kg, i.p.) in the forced swimming test. Besides that, the pretreatment of mice with prazosin (1 mg/kg, i.p., an alpha1-adrenoceptor antagonist) or yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) also prevented the anti-immobility effect of lamotrigine (30 mg/kg, i.p.). Moreover, the administration of subeffective doses of phenylephrine (5 mg/kg, i.p., an alpha1-adrenoceptor agonist) or clonidine (0.06 mg/kg, i.p., an alpha2-adrenoceptor agonist) was able to potentiate the action of a subeffective dose of lamotrigine (10 mg/kg, i.p.) in the forced swimming test. Thus, the present study suggests that the antidepressant-like effect of lamotrigine in the forced swimming test is related to the noradrenergic system, likely due to an activation of alpha1- and alpha2-postsynaptic adrenoceptors.
Asunto(s)
Antidepresivos/farmacología , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Triazinas/farmacología , Animales , Clonidina/farmacología , Femenino , Técnicas In Vitro , Lamotrigina , Ratones , Fenilefrina/farmacología , Natación , alfa-Metiltirosina/farmacologíaAsunto(s)
Analgésicos/farmacología , Ciclohexanoles/farmacología , Mononeuropatías/tratamiento farmacológico , Dolor/tratamiento farmacológico , Analgésicos/uso terapéutico , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ciclohexanoles/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Fenclonina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Nervio Ciático/lesiones , Clorhidrato de Venlafaxina , Vocalización Animal/efectos de los fármacos , alfa-Metiltirosina/farmacologíaRESUMEN
Prenatal malnutrition results in increased concentration and release of central noradrenaline, a neurotransmitter that is an important regulator of normal regressive events such as axonal pruning and synaptic elimination. This suggests that some of the functional disturbances in brain induced by prenatal malnutrition could be due at least in part to increased noradrenaline activity that may enhance regressive events during early stages of development. To test this hypothesis we studied whether chronic administration of alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase, to rats during gestation might prevent long-term deleterious effects of prenatal malnutrition on functional properties of interhemispheric connections of the visual cortex, and on asymmetry of visual evoked responses. The experiments were conducted on normal and malnourished rats 45-50 d of age. Prenatal malnutrition was induced by restricting the food consumption of pregnant rats to 40%, from d 8 postconception to parturition. At birth, prenatally malnourished rats had significantly greater whole-brain noradrenaline concentration as well as significantly enhanced noradrenaline release in the visual cortex. At 45-50 d of age, the malnourished group had a significantly smaller cortical area, exhibiting transcallosal evoked responses; in addition, the amplitude of these responses was significantly smaller. Malnourished rats showed a significant reduction of the normal interhemispheric asymmetry of visual evoked responses. The addition of 0.3% alpha-methyl-p-tyrosine to the diet of malnourished pregnant rats during the last 2 wk of gestation prevented functional disorders induced in the offspring by prenatal malnutrition on interhemispheric connectivity of visual areas and on interhemispheric bioelectrical asymmetry, probably by reducing the elevated brain noradrenaline activity and thereby restoring the normal trophic role of this neurotransmitter.