RESUMEN
Diabetes mellitus (DM) and major depressive disorder (MDD) are diseases that are expanding globally. Separately, each presents with several comorbidities for patients. When the two diseases present simultaneously in the same subject, there is a drastic worsening in the quality of life of the patient. This study reviewed the literature relating to the relationship between MDD and DM, bringing forward studies showing that DM develops due to MDD, and others that report the opposite. According to the studies reviewed, DM and MDD are both debilitating conditions that are associated with significant morbidity, mortality, and healthcare costs. When these two diseases coexist, the association results in a decreased adherence to treatment, poor metabolic control, higher rates of complications, a decrease in the quality of life for the patient, increased healthcare use and cost, increased disability and lost productivity, and an increased risk of death. Therefore, it becomes essential that there are larger studies targeting the association of these two diseases, as for the patient, preventing even one of them will ensure improvements in their quality of life.
Asunto(s)
Trastorno Depresivo Mayor/fisiopatología , Diabetes Mellitus/fisiopatología , Calidad de Vida , Animales , Comorbilidad , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/terapia , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapia , Costos de la Atención en Salud , HumanosRESUMEN
Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine's antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against oxidative stress, without affecting inflammation parameters.
Asunto(s)
Antioxidantes/farmacología , Encefalitis/prevención & control , Ketamina/farmacología , Estrés Oxidativo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Sirolimus/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Antidepresivos/farmacología , Masculino , Corteza Prefrontal/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures.
Asunto(s)
Estrés del Retículo Endoplásmico/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Inmunosupresores/farmacología , Ketamina/farmacología , Corteza Prefrontal/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Análisis de Varianza , Animales , Vías de Administración de Medicamentos , Inhibidores Enzimáticos/farmacología , Masculino , Ratas , Ratas WistarRESUMEN
The purpose of this study was to assess the effect of an enriched C-glycosyl flavonoids fraction (EFF-Cp) from Cecropia Pachystachya leaves on behavior, mitochondrial chain function, and oxidative balance in the brain of rats subjected to chronic mild stress. Male Wistar rats were divided into experimental groups (saline/no stress, saline/stress, EFF-Cp/no stress, and EFF-Cp/stress). ECM groups were submitted to stress for 40 days. On the 35th ECM day, EFF-Cp (50 mg/kg) or saline was administrated and the treatments lasted until the 42nd day. On the 41st and 42nd days, the animals were submitted to the splash test and the forced swim test. After these behavioral tests, the enzymatic activity of mitochondrial chain complexes and oxidative stress were analyzed. EFF-Cp reversed the depressive-like behavior induced by ECM. It also reversed the increase in thiobarbituric acid reactive species, myeloperoxidase activity, and nitrite/nitrate concentrations in some brain regions. The reduced activities of the antioxidants superoxide dismutase and catalase in some brain regions were also reversed by EFF-Cp. The most pronounced effect of EFF-Cp on mitochondrial complexes was an increase in complex IV activity in all studied regions. Thus, it is can be concluded that EFF-Cp exerts an antidepressant-like effect and that oxidative balance may be an important physiological process underlying these effects.
Asunto(s)
Antidepresivos/farmacología , Flavonoides/química , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Estrés Psicológico/fisiopatología , Animales , Enfermedad Crónica , Creatina Quinasa/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Aseo Animal/efectos de los fármacos , Masculino , Nitritos/metabolismo , Oxidorreductasas/metabolismo , Peroxidasa/metabolismo , Hojas de la Planta/química , Carbonilación Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Natación/psicología , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
BACKGROUND: Ketamine, an antagonist of N-methyl-d-aspartate (NMDA) receptors, has presented antidepressant effects in basic and clinical studies. The MAPK kinase (MEK) signaling pathway could be a target for novel antidepressant drugs and an important pathway involved in neuronal plasticity. Thus, this study evaluated the effects of the administration of ketamine on the phosphorylation of TrKB and CREB, and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc) rats, after the inhibition of MAPK pathway (PD184161). METHODS: Male adult Wistar rats were submitted to a surgical procedure to receive a single dose of a pharmacological inhibitor of MAPK (PD184161) at a dose of (0.1µg/µl) or vehicle. Then, they were divided: 1) vehicle+saline; 2) inhibitor PD184161+saline; 3) vehicle+ketamine 15mg/kg; and 4) inhibitor PD184161+ketamine 15mg/kg. RESULTS: MEK inhibitor and ketamine increased the phosphorylation of the transcription factor cAMP response element-binding protein (pCREB) and neurotrophic factor/tropomyosin related kinase B receptor (pTrKB) in the PFC, and decreased pCREB in the hippocampus. The MEK inhibitor abolished ketamine's effects in the hippocampus. In the amygdala, pCREB was decreased, and pTrKB was increased after MEK inhibitor plus ketamine. Ketamine increased the thiobarbituric acid reactive species (TBARS) in the PFC, hippocampus, amygdala, and NAc; MEK inhibitor antagonized these effects. The carbonyl was increased in the PFC by both ketamine and MEK inhibitor, but inhibitor infusion plus ketamine administration reduced this effect. In the amygdala, MEK inhibitor increased carbonyl. CONCLUSION: Ketamine's effects on pCREB, pTrKB, and oxidative stress are mediated, at least in part, by a mechanism dependent of MAPK signaling inhibition.
Asunto(s)
Compuestos de Anilina/administración & dosificación , Benzamidas/administración & dosificación , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ketamina/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Estrés Oxidativo/fisiología , Receptor trkB/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Infusiones Intravenosas , Masculino , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Ratas , Ratas WistarRESUMEN
Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes.
Asunto(s)
Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Trastorno Depresivo/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Páncreas/efectos de los fármacos , Acetilcisteína/farmacología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Deferoxamina/farmacología , Trastorno Depresivo/metabolismo , Trastorno Depresivo/patología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/psicología , Depuradores de Radicales Libres/farmacología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Páncreas/metabolismo , Páncreas/patología , Ratas , Ratas Wistar , Sideróforos/farmacologíaRESUMEN
This study aimed at investigating the effects of chronic mild stress on DNA damage, NMDA receptor subunits and glutamate transport levels in the brains of rats with an anxious phenotype, which were selected to represent both the high-freezing (CHF) and low-freezing (CLF) lines. The anxious phenotype induced DNA damage in the hippocampus, amygdala and nucleus accumbens (NAc). CHF rats subjected to chronic stress presented a more pronounced DNA damage in the hippocampus and NAc. NMDAR1 were increased in the prefrontal cortex (PC), hippocampus and amygdala of CHF, and decreased in the hippocampus, amygdala and NAc of CHF stressed. NMDAR2A were decreased in the amygdala of the CHF and stressed; and increased in CHF stressed. NMDRA2A in the NAc was increased after stress, and decreased in the CLF. NMDAR2B were increased in the hippocampus of CLF and CHF. In the amygdala, there was a decrease in the NMDAR2B for stress in the CLF and CHF. NMDAR2B in the NAc were decreased for stress and increased in the CHF; in the PC NMDAR2B increased in the CHF. EAAT1 increased in the PC of CLF+stress. In the hippocampus, EAAT1 decreased in all groups. In the amygdala, EAAT1 decreased in the CLF+stress and CHF. EAAT2 were decreased in the PC for stress, and increased in CHF+control. In the hippocampus, the EAAT2 were increased for the CLF and decreased in the CLF+stress. In the amygdala, there was a decrease in the EATT2 in the CLF+stress and CHF. These findings suggest that an anxious phenotype plus stress may induce a more pronounced DNA damage, and promote more alterations in the glutamatergic system. These findings may help to explain, at least in part, the common point of the mechanisms involved with the pathophysiology of depression and anxiety.
Asunto(s)
Ansiedad/metabolismo , Encéfalo/metabolismo , Daño del ADN , Ácido Glutámico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Psicológico/metabolismo , Animales , Ansiedad/genética , Ansiedad/patología , Encéfalo/patología , Depresión/genética , Depresión/metabolismo , Depresión/patología , Transportador 1 de Aminoácidos Excitadores/genética , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Transportador 2 de Aminoácidos Excitadores/metabolismo , Ácido Glutámico/genética , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/genética , Especificidad de la Especie , Estrés Psicológico/genética , Estrés Psicológico/patologíaRESUMEN
Studies have suggested that ketamine, a nonselective NMDA receptor antagonist, could be a new drug in the treatment of major depression, but the way ketamine presents such effects remains to be elucidated. Therefore, the objective of this paper was to evaluate the effects of ketamine treatment on parameters related to depression in the brain of adult rats subjected to an animal model of depression. The animals were divided into: non-deprived + saline; non-deprived + ketamine; deprived + saline; deprived + ketamine. Treatments involving ketamine (15 mg/kg) were administered once a day during 14 days in the animal's adult phase. After treatment, the brain derived-neurotrophic factor (BDNF) levels, oxidative stress and energy metabolism activity were evaluated in brain structures of rats involved in the circuit of depression. In the amygdala, hippocampus and nucleus accumbens (NAc), a reduction in BDNF levels was observed in deprived rats, but the animals treated with ketamine reversed the effects of this animal model only in the amygdala and NAc. In addition to this, the complex I activity, in deprived rats, was diminished in the prefrontal cortex (PFC) and amygdala; in the PFC and hippocampus, the complex II-III was diminished in deprived rats; still the administration of ketamine increased the complex IV activity in the PFC and amygdala of rats submitted to the maternal deprivation. In deprived rats, the creatine kinase activity was reduced in the PFC and amygdala, however the administration of ketamine reversed this decrease in the amygdala. The malondialdehyde (MDA) equivalents were increased in non-deprived rats treated with ketamine in the PFC and NAc. Carbonyl levels in the PFC were diminished in control rats that received saline. Though ketamine treatment reversed this effect in deprived rats in the PFC and hippocampus. Still, in NAc, the carbonyl levels were diminished in deprived rats. The superoxide dismutase (SOD) activity was increased in control rats that received ketamine in the PFC and NAc, and were diminished in deprived rats that received saline or ketamine in the PFC and hippocampus. These findings may help to explain that dysfunctions involving BDNF, oxidative stress and energy metabolism within specific brain areas, may be linked with the pathophysiology of depression, and antidepressant effects of ketamine can be positive, at least partially due to the control of these pathways.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ketamina/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Análisis de Varianza , Animales , Animales Recién Nacidos , Creatina Quinasa/metabolismo , Depresión/patología , Modelos Animales de Enfermedad , Femenino , Masculino , Privación Materna , Embarazo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido TiobarbitúricoRESUMEN
A growing body of evidence points toward an association between the glutamatergic system, as well as immune system dysregulation and major depression. So, the present study was aimed at evaluating the behavioral and molecular effects of the ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) receptor of glutamate in maternally deprived adult rats. In deprived rats treated with saline, we observed an increase in the immobility time; however, ketamine treatment reversed this effect, decreasing immobility time. In addition, maternal deprivation induced an increase in cytokines: TNF-α and IL-1 in serum, and in IL-6 in serum and cerebrospinal fluid (CSF). Interestingly, ketamine treatment reduced the levels of all the cytokines in deprived rats. In conclusion, these findings further support a relationship between immune activation and depression. Considering the action of ketamine, this study suggested that antagonists of the NMDA receptor, such as ketamine, could exert their effects by modulation of the immune system.
Asunto(s)
Antidepresivos/uso terapéutico , Citocinas/sangre , Depresión/tratamiento farmacológico , Ketamina/uso terapéutico , Privación Materna , Animales , Citocinas/líquido cefalorraquídeo , Depresión/inmunología , Depresión/psicología , Femenino , Interleucina-1/sangre , Interleucina-6/sangre , Interleucina-6/líquido cefalorraquídeo , Masculino , Ratas Wistar , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Studies have been suggested that minocycline can be a potential new agent for the treatment of depression. In addition, both oxidative stress and energy metabolism present an important role in pathophysiology of depression. So, the present study was aimed to evaluate the effects of minocycline on stress oxidative parameters and energy metabolism in the brain of adult rats submitted to the chronic mild stress protocol (CMS). After CMS Wistar, both stressed animals as controls received twice ICV injection of minocycline (160 µg) or vehicle. The oxidative stress and energy metabolism parameters were assessed in the prefrontal cortex (PF), hippocampus (HIP), amygdala (AMY) and nucleus accumbens (Nac). Our findings showed that stress induced an increase on protein carbonyl in the PF, AMY and NAc, and mynocicline injection reversed this alteration. The TBARS was increased by stress in the PF, HIP and NAc, however, minocycline reversed the alteration in the PF and HIP. The Complex I was incrased in AMY by stress, and minocycline reversed this effect, however reduced Complex I activity in the NAc; Complex II reduced in PF and AMY by stress or minocycline; the Complex II-III increased in the HIP in stress plus minocycline treatment and in the NAc with minocycline; in the PF and HIP there were a reduced in Complex IV with stress and minocycline. The creatine kinase was reduced in AMY and NAc with stress and minocycline. In conclusion, minocycline presented neuroprotector effects by reducing oxidative damage and regulating energy metabolism in specific brain areas.
Asunto(s)
Antioxidantes/farmacología , Química Encefálica/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Minociclina/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Psicológico/metabolismo , Animales , Enfermedad Crónica , Creatina Quinasa/metabolismo , Complejo I de Transporte de Electrón/efectos de los fármacos , Complejo II de Transporte de Electrones/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Estrés Psicológico/tratamiento farmacológico , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Anxiety disorders pose one of the largest threats to global mental health, and they predominantly emerge early in life. Social anxiety disorder, also known as social phobia, is the most common of all anxiety disorders. Moreover, it has severe consequences and is a disabling disorder that can cause an individual to be unable to perform the tasks of daily life. Social anxiety disorder is associated with the subsequent development of major depression and other mental diseases, as well as increased substance abuse. Although some neurobiological alterations have been found to be associated with social anxiety disorder, little is known about this disorder. Animal models are useful tools for the investigation of this disorder, as well as for finding new pharmacological targets for treatment. Thus, this review will highlight the main animal models of anxiety associated with social phobia.
Asunto(s)
Modelos Animales de Enfermedad , Trastornos Fóbicos/fisiopatología , Animales , Trastorno Depresivo Mayor/etiología , Humanos , Trastornos Mentales/etiología , Trastornos Fóbicos/complicaciones , Trastornos Fóbicos/tratamiento farmacológico , Trastornos Relacionados con Sustancias/etiología , Estudios de Validación como AsuntoRESUMEN
Studies have pointed to a relationship between MAPK kinase (MEK) signaling and the behavioral effects of antidepressant drugs. So, in the present study we examined the behavioral and molecular effects of ketamine, an antagonist of the N-methyl-d-aspartate receptor (NMDA), which has been shown to have an antidepressant effect after the inhibition of MEK signaling in Wistar rats. Our results showed that acute administration of the MEK inhibitor PD184161, produced depressive-like behavior and stopped antidepressant-like effects of ketamine in the forced swimming test. The phosphorylation of extracellular signal-regulated kinase 1/2 (pERK 1/2) was decreased by PD184161 in the amygdala and nucleus accumbens, and the effects of ketamine on pERK 1/2 in the prefrontal cortex and hippocampus were inhibited by PD184161. The ERK 2 levels were decreased by PD184161 in the nucleus accumbens; and the effects of ketamine were blocked in this brain area. The p38 protein kinase (p38MAPK) and proBDNF were inhibited by PD184161, and the MEK inhibitor prevented the effects of ketamine in the nucleus accumbens. In addition, ketamine increased pro-BDNF levels in the hippocampus. In conclusion, our findings demonstrated that an acute blockade of MAPK signaling lead to depressive-like behavior and stopped the antidepressant response of ketamine, suggesting that the effects of ketamine could be mediated, at least in part, by the regulation of MAPK signaling in these specific brain areas.
Asunto(s)
Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Trastorno Depresivo/tratamiento farmacológico , Ketamina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Compuestos de Anilina , Animales , Benzamidas , Western Blotting , Encéfalo/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastorno Depresivo/fisiopatología , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Pruebas Neuropsicológicas , Fosforilación/efectos de los fármacos , Ratas Wistar , Natación , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Studies indicate that histone deacetylation is important for long term changes related to stress and antidepressant treatment. The present study aimed to evaluate the effects of the classic antidepressant imipramine, and of an antagonist of the N-methyl-d-asparte (NMDA) receptor, ketamine, on behavior and histone deacetylase (HDAC) activity in the brains of maternally deprived adult rats. To this aim, deprived and non-deprived (control) male Wistar rats were divided into the following groups: non-deprived+saline; non-deprived+imipramine (30 mg/kg); non-deprived+ketamine (15 mg/kg); deprived+saline; deprived+imipramine (30 mg/kg); and deprived+ketamine (15 mg/kg). The drugs were administrated once a day for 14 days during their adult phase. Their behavior were then assessed using the forced swimming and open field tests. In addition, the HDAC activity was evaluated in the prefrontal cortex, hippocampus, amygdala and nucleus accumbens using the kit ELISA-sandwich test. In deprived rats treated with saline, we observed an increase in the immobility time, but treatments with imipramine and ketamine were able to reverse this alteration, decreasing the immobility time. Also, there was a decrease on number of crossings with imipramine treatment in non-deprived rats, and an increase on number of crossings with ketamine treatment in deprived rats. The HDAC activity did not alter in the prefrontal cortex, hippocampus and amygdala by deprivation or via treatment with imipramine or ketamine. However, in the nucleus accumbens we observed an increase of HDAC activity in the deprived rats, and interestingly, imipramine and ketamine treatments were able to decrease HDAC activity in this brain area. These findings provide a novel insight into the epigenetic regulation of histone deacetylase in the nucleus accumbens caused by imipramine and ketamine, and indicate that molecular events are necessary to reverse specific stress-induced behavior.
Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Histonas/metabolismo , Imipramina/farmacología , Ketamina/farmacología , Privación Materna , Núcleo Accumbens/efectos de los fármacos , Acetilación , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Conducta Animal/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , NataciónRESUMEN
A growing body of evidence is pointing toward an association between immune molecules, as well brain-derived neurotrophic factor (BDNF) and the depression. The present study was aimed to evaluate the behavioral and molecular effects of the antidepressant imipramine in maternally deprived adult rats. To this aim, maternally deprived and non-deprived (control group) male rats were treated with imipramine (30mg/kg) once a day for 14 days during their adult phase. Their behavior was then assessed using the forced swimming test. In addition to this, IL-10, TNF-α and IL-1ß cytokines were assessed in the serum and cerebrospinal fluid (CSF). In addition, BDNF protein levels were assessed in the prefrontal cortex, hippocampus and amygdala. In deprived rats treated with saline was observed an increase on immobility time, compared with non-deprived rats treated with imipramine (p<0.05). Deprived rats treated with saline presented a decrease on BDNF levels in the amygdala (p<0.05), compared with all other groups. The IL-10 levels were decreased in the serum (p<0.05). TNF-α and IL-1ß levels were increased in the serum and CSF of deprived rats treated with saline (p<0.05). Interestingly, imipramine treatment reversed the effects of maternal deprivation on BDNF and cytokines levels (p<0.05). Finally, these findings further support a relationship between immune activation, neurotrophins and the depression, and considering the action of imipramine, it is suggested that classic antidepressants could exert their effects by modulating the immune system.
Asunto(s)
Antidepresivos Tricíclicos/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Imipramina/administración & dosificación , Privación Materna , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Masculino , Embarazo , Ratas , Ratas WistarRESUMEN
Animal models of chronic stress represent valuable tools by which to investigate the behavioral, endocrine and neurobiological changes underlying stress-related psychopathologies, such as major depression, and the efficacy of antidepressant therapies. The present study was aimed at investigating the neurochemical effects of the antidepressant tianeptine in rats exposed to the chronic stress model. To this aim, rats were subjected to 40days of chronic unpredictable stressful stimuli, after which the animals received saline or tianeptine (15mg/kg) once a day for 7days. Additionally, IL-6, IL-1, TNF-α levels and oxidative stress parameters were assessed in the prefrontal cortex (PFC), hippocampus (HPC), amygdala (AMY) and nucleus accumbens (NAc) in all of the experimental groups studied. The results indicated that chronic mild stress and tianeptine did not exercise any effects on cytokines in all of the structures studied; in the PFC and AMY thiobarbituric acid reactive substances (TBARS) levels were decreased in control rats treated with tianeptine in the HPC; superoxide dismutase (SOD) activity was found to have decreased in stressed rats treated with saline in the PFC, HPC, AMY and NAc, and tianeptine reversed this effect; catalase (CAT) activity was found to have decreased in the PFC, HPC and NAc of stressed rats treated with saline, but was shown to have increased in stressed rats treated with tianeptine, and tianeptine also reversed the decreases in CAT activity in stressed rats treated with saline, suggesting that tianeptine exerted antioxidant activity. In conclusion, the present findings open new vistas on the pharmacological activity of tianeptine, in particular, concerning its ability to attenuate oxidative stress.