RESUMEN

The role of intestinal microbiota in the genesis of mental health has received considerable attention in recent years, given that probiotics are considered promising therapeutic agents against major depressive disorder. Komagataella pastoris KM71H is a yeast with probiotic properties and antidepressant-like effects in animal models of depression. Hence, we evaluated the antidepressant-like effects of K. pastoris KM71H in a model of antibiotic-induced intestinal dysbiosis in male Swiss mice. The mice received clindamycin (200 µg, intraperitoneal) and, after 24 h, were treated with K. pastoris KM71H at a dose of 8 log CFU/animal by intragastric administration (ig) or PBS (vehicle, ig) for 14 consecutive days. Afterward, the animals were subjected to behavioral tests and biochemical analyses. Our results showed that K. pastoris KM71H administration decreased the immobility time in the tail suspension test and increased grooming activity duration in the splash test in antibiotic-treated mice, thereby characterizing its antidepressant-like effect. We observed that these effects of K. pastoris KM71H were accompanied by the modulation of the intestinal microbiota, preservation of intestinal barrier integrity, and restoration of the mRNA levels of occludin, zonula occludens-1, zonula occludens-2, and toll-like receptor-4 in the small intestine, and interleukin-1ß in the hippocampi of mice. Our findings provide solid evidence to support the development of K. pastoris KM71H as a new probiotic with antidepressant-like effects.

Asunto(s)

Trastorno Depresivo Mayor , Microbioma Gastrointestinal , Masculino , Animales , Ratones , Antibacterianos/farmacología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico

RESUMEN

AIMS: The protective effects of Bacillus amyloliquefaciens(CCT7935), Bacillus subtilis(CCT7935), Bacillus licheniformis (CCT 7836), and Bacillus coagulans (CCT 0199) against lipopolysaccharide (LPS)-induced intestinal inflammation were investigated. METHODS AND RESULTS: Male Swiss mice were assigned into six groups: control group, LPS group, LPS + B. subtilis (CCT7935) group, LPS +   B. licheniformis (CCT 7836) group, LPS +   B. amyloliquefaciens (CCT7935) group, and LPS   + B. coagulans (CCT 0199) group. Each mouse of the groups Bacillus received 1 × 109 colony-forming units of Bacillus once daily by oral gavage during 30 days. Twenty-four hours after the last dose of Bacillus, all groups, except the control group, were intraperitoneally injected with LPS in the single dose of 15 mg kg-1. The mice were euthanized 24 h after the LPS administration. Histological alterations, myeloperoxidase activity, and nitrite levels were analyzed in the gut of mice and the inflammatory cytokines were analyzed in the gut and in the blood. The results demonstrate that the mice challenged with LPS presented the villi shortened and damaged, which were significantly protected by B. coagulans and B. amyloliquefaciens. Furthermore, all Bacillus tested were effective in preventing against the increase of myeloperoxidase activity, while B. amyloliquefaciens and B. subtilis prevented the increase of nitrite and IL-1ß levels in the gut of mice induced with LPS was decreased only B. subtilis. LPS also elevated the IL-1 ß, IL-6, and IL-10 levels in the blood, and these alterations were significantly suppressed by Bacillus, especially by B. subtilis. CONCLUSIONS: The study suggests that the Bacillus investigated in this study might be effective therapeutic agents for preventing intestinal inflammation, because they decrease the inflammatory process an protect against tissue damage.

Asunto(s)

Bacillus , Probióticos , Animales , Ratones , Masculino , Lipopolisacáridos , Peroxidasa , Nitritos , Probióticos/farmacología , Inflamación/inducido químicamente , Inflamación/prevención & control

RESUMEN

Stress is an important factor in the development of several human pathologies. The response of rodents and humans to stress depends on many factors; some people and rodents develop stress-related mood disorders, such as depression and anxiety in humans, depression-like and anxiety-like behavior in mice and rats, while others report no new psychological symptoms in response to chronic or acute stress, and are considered susceptible and resilient to stress, respectively. Resilience is defined as the ability to thrive in the face of adversity and is a learned process that can help protect against occupational stressors and mental illnesses. There is growing interest in the underlying mechanisms involved in resilience and vulnerability to depression caused by stress, and some studies have demonstrated that individual variability in the way animals and humans respond to stress depends on several mechanisms, such as oxidative stress, neuronal plasticity, immunology and genetic factors, among others not discussed in this review, this review provides a general overview about this mechanism.

RESUMEN

Aging is characterized by several neurochemical modifications involving structural proteins and neurotransmitters. Exercise has been recognized as an enhancer of overall health; whereas, diphenyl diselenide (PhSe)2 has been reported to have antioxidant, anti-inflammatory, and neuroprotective effects in rodents. A combination of pharmacological and non-pharmacological interventions has been proposed to prevent the aging effects. This study aimed to determine the swimming exercise and (PhSe)2 dietary supplementation synergic effects on the [3H] γ-aminobutyric acid (GABA) uptake in aged rats. Male Wistar rats (24 months) received 1 ppm of (PhSe)2 supplemented in the standard chow for 4 weeks. Rats were subjected to swimming training (20 min per day for 4 weeks). After 4 weeks, the [3H]GABA uptake was determined in samples of cerebral cortex and striatum of rats. The results of the present study demonstrate that the association of (PhSe)2-supplemented diet and swimming exercise was effective against the decrease of cerebral cortical and striatal [3H]GABA uptake in aged rats. The association of (PhSe)2 dietary supplementation with swimming exercise modulated the GABA uptake in cerebral structures of aged rats.

Asunto(s)

Suplementos Dietéticos , Natación , Animales , Derivados del Benceno , Corteza Cerebral , Dieta , Masculino , Compuestos de Organoselenio , Ratas , Ratas Wistar , Ácido gamma-Aminobutírico

RESUMEN

Many studies have suggested that imbalance of the gut microbial composition leads to an increase in pro-inflammatory cytokines and promotes oxidative stress, and this are directly associated with neuropsychiatric disorders, including major depressive disorder (MDD). Clinical data indicated that the probiotics have positive impacts on the central nervous system and thus may have a key role to treatment of MDD. This study examined the benefits of administration of Komagataella pastoris KM71H (8 log UFC·g-1/animal, intragastric route) in attenuating behavioral, neurochemical, and neuroendocrine changes in animal models of depressive-like behavior induced by repeated restraint stress and lipopolysaccharide (0.83 mg/kg). We demonstrated that pretreatment of mice with this yeast prevented depression-like behavior induced by stress and an inflammatory challenge in mice. We believe that this effect is due to modulation of the permeability of the blood-brain barrier, restoration in the mRNA levels of the Nuclear factor kappa B, Interleukin 1ß, Interferon γ, and Indoleamine 2 3-dioxygenase, and prevention of oxidative stress in the prefrontal cortices, hippocampi, and intestine of mice and of the decrease the plasma corticosterone levels. Thus, we conclude that K. pastoris KM71H has properties for a new proposal of probiotic with antidepressant-like effect, arising as a promising therapeutic strategy for MDD.

Asunto(s)

Antidepresivos/uso terapéutico , Depresión/terapia , Trastorno Depresivo Mayor/terapia , Probióticos/uso terapéutico , Saccharomycetales , Estrés Psicológico/terapia , Animales , Antidepresivos/farmacología , Conducta Animal , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Corticosterona/sangre , Depresión/metabolismo , Depresión/patología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/patología , Modelos Animales de Enfermedad , Expresión Génica , Intestino Delgado/anatomía & histología , Intestino Delgado/metabolismo , Lipopolisacáridos , Masculino , Ratones , Estrés Oxidativo , Probióticos/farmacología , Bazo/patología , Estrés Psicológico/metabolismo , Estrés Psicológico/patología

RESUMEN

In this contribution, a metal- and base-free protocol has been developed for the synthesis of phosphorochalcogenoates (Se and Te) by using DMSO as solvent at 50 °C. A variety of phosphorochalcogenoates were prepared from diorganyl dichalcogenides and H-phosphonates, leading to the formation of a Chal-P(O) bond, in a rapid procedure with good to excellent yields. A full structural elucidation of products was accessed by 1D and 2D NMR, IR, CGMS, and HRMS analyses, and a stability evaluation of the phosphorochalcogenoates was performed for an effective operational description of this simple and feasible method. Typical 77Se{1H} (δSe = 866.0 ppm), 125Te{1H} (δTe = 422.0 ppm) and 31P{1H} (δP = -1.0, -13.0 and -15.0 ppm) NMR chemical shifts were imperative to confirm the byproducts, in which this stability study was also important to select some products for pharmacological screening. The phosphorochalcogenoates were screened in vitro and ex vivo tests for the antioxidant potential and free radical scavenging activity, as well as to investigation toxicity in mice through of the plasma levels of markers of renal and hepatic damage. The pharmacological screening of phosphorochalcogenoates indicated that compounds have antioxidant propriety in different assays and not changes plasma levels of markers of renal and hepatic damage, with excision of 3g compound that increased plasma creatinine levels and decreased plasma urea levels when compared to control group in the blood mice. Thus, these compounds can be promising synthetic antioxidants that provide protection against oxidative diseases.

Asunto(s)

Antioxidantes/síntesis química , Depuradores de Radicales Libres/síntesis química , Tecnología Química Verde/métodos , Organofosfonatos/síntesis química , Compuestos de Selenio/química , Telurio/química , Animales , Antioxidantes/farmacología , Biomarcadores/sangre , Encéfalo , Calcógenos/química , Evaluación Preclínica de Medicamentos , Depuradores de Radicales Libres/farmacología , Radicales Libres/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Riñón , Hígado , Masculino , Ratones , Organofosfonatos/farmacología , Oxidación-Reducción , Solventes/química , Relación Estructura-Actividad , Superóxido Dismutasa/metabolismo

RESUMEN

Exposure to stress highly correlates with the emergence of mood-related illnesses. Therefore, the present study was designed to characterize the acute and chronic effects of 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI) on depressive-like behavior induced by repeated forced swim stress (FSS) in male adult Swiss mice. In the repeated FSS, mice were placed in water to swim for a single trial during a 15-min period. Twenty-four hours after the first FSS, the animals were placed in water to swim through a series of four trials, and each of them swam for 6 min long; between each trial, mice were towel dried and returned to their home cage for 6 min. In addition, the oxidative stress in the prefrontal cortex and hippocampus and corticosterone levels of plasma of mice were investigated. The animals exposed to FSS were treated with CM in two different protocols. In protocol 1, CMI [1 and 10 mg/kg, intragastric (i.g.) route] or fluoxetine, a positive control (10 mg/kg, i.g. route), were administered 30 min before of sections of repeated FSS in both days of stress. After the last section of repeated FSS, the mice performed first the spontaneous locomotor activity and after the tail suspension test. In protocol 2, CMI or fluoxetine (1 mg/kg, i.g. route) was administered for 20 days after the exposition of repeated FSS. The spontaneous locomotor activity, tail suspension, and forced swimming tests were performed in this order after 24 h of last administration of CMI or fluoxetine. The euthanasia of animals was performed after the behavioral tests. CMI and fluoxetine abolished the depressive-like behavior induced by repeated FSS in mice in the two different treatments. CMI modulated the oxidative stress in the prefrontal cortices and hippocampi of mice subjected to repeated FSS. Mice subjected to repeated FSS had an increase in the corticosterone levels and CMI regulated the levels of this glucocorticoid. These findings demonstrate that CMI was effective to abolish the depressive-like behavior induced by repeated FSS, which was accompanied by changes in the corticosterone levels and oxidative stress of prefrontal cortices and hippocampi of mice.

RESUMEN

Pyrazoles represent a significant class of heterocyclic compounds that exhibit pharmacological properties. The present study aimed to investigate the antioxidant potential of pyrazol derivative compounds in brain of mice in vitro and the effect of pyrazol derivative compounds in the oxidative damage and toxicity parameters in mouse brain and plasma of mice. The compounds tested were 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazol (1a), 3,5-dimethyl-4-(phenylselanyl)-1H-pyrazole (2a), 4-((4-methoxyphenyl)selanyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (3a), 4-((4-chlorophenyl)selanyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (4a), 3,5-dimethyl-1-phenyl-4-(phenylthio)-1H-pyrazole (1b), 3,5-dimethyl-4-(phenylthio)-1H-pyrazole (2b), 4-((4-methoxyphenyl)thio)-3,5-dimethyl-1-phenyl-1H-pyrazole (3b), 4-((4-chlorophenyl)thio)-3,5-dimethyl-1-phenyl-1H-pyrazole (4b), and 3,5-dimethyl-1-phenyl-1H-pyrazole (1c). In vitro, 4-(arylcalcogenyl)-1H-pyrazoles, at low molecular range, reduced lipid peroxidation and reactive species in mouse brain homogenates. The compounds also presented ferric-reducing ability as well nitric oxide-scavenging activity. Especially compounds 1a, 1b, and 1c presented efficiency to 1,1-diphenyl-2-picryl-hydrazyl-scavenging activity. Compounds 1b and 1c presented 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)-scavenging activity. In vivo assays demonstrated that compounds 1a, 1b, and 1c (300 mg/kg, intragastric, a single administration) did not cause alteration in the of δ-aminolevulinic acid dehydratase activity, an enzyme that exhibits high sensibility to prooxidants situations, in the brain, liver, and kidney of mice. Compound 1c reduced per se the lipid peroxidation in liver and brain of mice. Toxicological assays demonstrate that compounds 1a, 1b, and 1c did not present toxicity in the aspartate aminotransferase, alanine aminotransferase, urea, and creatinine levels in the plasma. In conclusion, the results demonstrated the antioxidant action of pyrazol derivative compounds in in vitro assays. Furthermore, the results showed low toxicity of compounds in in vivo assays.

Asunto(s)

Corteza Cerebral/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Peroxidación de Lípido/efectos de los fármacos , Pirazoles/farmacología , Administración Oral , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Evaluación Preclínica de Medicamentos , Depuradores de Radicales Libres/química , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Modelos Animales , Pirazoles/química , Especies Reactivas de Oxígeno/metabolismo , Selenio/química , Azufre/química , Pruebas de Toxicidad Aguda

RESUMEN

The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5-25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3-5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect.

Asunto(s)

Amnesia/prevención & control , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Quinolinas/farmacología , Amnesia/inducido químicamente , Animales , Conducta Animal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Proteínas de la Membrana/genética , Ratones , Actividad Motora/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo , Corteza Prefrontal/efectos de los fármacos , Escopolamina/toxicidad , Transducción de Señal

RESUMEN

This work evaluated the in vitro effect of thiazolidin-4-ones on the activity of AChE (total and isoforms) isolated from the cerebral cortex, hippocampus, and lymphocytes. Kinetic parameters were evaluated and molecular docking was performed. Our results showed that thiazolidinones derived from 4-(methylthio)benzaldehyde (1) and from 4-(methylsulfonyl)benzaldehyde (2) were capable of inhibiting the AChE activity in vitro. Three compounds, two with a propylpiperidine (1b and 2b) moiety and one with a 3-(diethylamino)propyl (1c) moiety showed IC50 values of 13.81 µM, and 3.13 µM (1b), 55.36 µM and 44.33 µM (1c) for cerebral cortex and hippocampus, respectively, and 3.11 µM for both (2b). Enzyme kinetics revealed that the type of AChE inhibition was mixed. Compound 1b inhibited the G1 and G4 AChE isoforms, while compounds 1c and 2b selectively inhibited the G4 isoform. Molecular docking showed a possible three-dimensional fit into the enzyme. Our findings showed that these thiazolidin-4-ones, especially those containing the propylpiperidine core, have a potential cholinesterase inhibitory activity and can be considered good candidates for future Alzheimer's therapy.

Asunto(s)

Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Tiazolidinas/farmacología , Acetilcolinesterasa/química , Animales , Dominio Catalítico , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Hipocampo/efectos de los fármacos , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Cinética , Linfocitos/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Ratas Wistar , Tiazolidinas/síntesis química , Tiazolidinas/metabolismo

RESUMEN

Oxidative stress and neuroinflammation are found both in diabetes mellitus and major depressive disorder (MDD). In addition to damage in peripheral organs, such as liver and kidney, diabetic patients have a higher risk of developing depression. In this sense, the objective of the present study was to characterize the antidepressant-like effect of a selenium-containing compound, the 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI), in streptozotocin (STZ)-induced diabetic mice. STZ (200 mg/kg, i.p.) was used to induce diabetes mellitus type I, and after seven days, the administration of MFSeI (10 mg/kg, i.g.) was initiated and followed for the next 14 days. Twenty-four hours after the last administration of MFSeI, the behavioral tests were performed, followed by euthanasia. The treatment with MFSeI was able to reverse the hyperglycemia induced by STZ. MFSeI also decreased the plasma levels of biomarkers of liver and kidney damage. Importantly, MFSeI reversed the depression-like behavior induced by STZ in the tail suspension test and forced swimming test without promoting locomotor alterations. Furthermore, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortex (PFC), hippocampus (HC), liver, and kidney of STZ-treated mice. Treatment with MFSeI also decreased the expression of tumor necrosis factor-alpha, inducible nitric oxide synthase and indoleamine 2,3-dioxygenase, while increasing the expression of interleukin-10, insulin receptor substrate-1 and glucose transport-4 in the PFC and HC of mice. Taken together, the results indicate the effectiveness of MFSeI against depression-like behavior and central and peripheral complications caused by diabetes in mice.

Asunto(s)

Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Depresión/tratamiento farmacológico , Diabetes Mellitus Experimental/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Indoles/farmacología , Inflamación/tratamiento farmacológico , Compuestos de Organoselenio/farmacología , Animales , Depresión/sangre , Depresión/inmunología , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inmunología , Hipocampo/efectos de los fármacos , Hiperglucemia/sangre , Hiperglucemia/inmunología , Indoles/administración & dosificación , Inflamación/sangre , Inflamación/inmunología , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Ratones , Compuestos de Organoselenio/administración & dosificación , Selenio

RESUMEN

Although the pathophysiology of major depression disorder (MDD) is still poorly understood, mounting evidence suggests that the brains of depressed patients are under oxidative stress, leading to depressive symptoms that may include anxiety and cognitive impairment. This study aimed to investigate if the seleno-organic compound 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) reverses the depression- and anxiogenic-like behaviour, cognitive impairment and oxidative stress induced by the intra-cerebroventricular injection of streptozotocin (STZ; 0.2 mg/4 µl/per mouse) in Swiss male mice. Twenty-four hours after the STZ injection, mice were treated with MFSeI (10 mg/kg, intra-gastrically), or vehicle solution, once daily for seven days. The behavioural tests were performed 30 min after the final MFSeI administration, followed by euthanasia and collection of the cerebral cortex and hippocampus. Administration of MFSeI reversed the depression- and anxiogenic-like behaviour and cognitive impairment induced by STZ, in mice. Neurochemical analyses demonstrated that MFSeI reversed the STZ-increased levels of reactive species, nitrite, lipid peroxidation and acetylcholinesterase activity in the cerebral cortex and hippocampus of mice. Moreover, a single administration of MFSeI (300 mg/kg, intra-gastrically) did not cause acute toxicity in Swiss male mice. Altogether, our data suggest that MFSeI exhibits antidepressant- and anxiolytic-like effects and improves the cognition of STZ-treated mice, without any toxicity.

Asunto(s)

Ansiolíticos/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Indoles/química , Indoles/farmacología , Estrés Nitrosativo/efectos de los fármacos , Selenio/química , Estreptozocina/farmacología , Acetilcolinesterasa/metabolismo , Animales , Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Ansiedad/tratamiento farmacológico , Corteza Cerebral/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Depresión/inducido químicamente , Hipocampo/metabolismo , Indoles/administración & dosificación , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Selenio/deficiencia , Estreptozocina/administración & dosificación

RESUMEN

Monosodium glutamate (MSG), a food flavor enhancer used worldwide, has been studied because it may cause neurotoxicity, which is associated with oxidative stress. The aim of this study was to investigate whether spinal cord and brain regions are affected by oxidative stress and the temporal profile of nociceptive responses induced by MSG in newborn and adult rats. The newborn (post natal day, PND 1) Wistar rats received ten subcutaneous injections of MSG (4.0 g/kg) or saline solution. At PND 3, 11 or 90, the rats performed nociceptive tests and parameters of oxidative stress were evaluated in samples of spinal cord and brain regions. Adult rats (PND 90) were injected with MSG (4.0 g/kg, 10 injections) or saline solution, but MSG did not induce nociception or oxidative stress. The neonatal administration of MSG increased nociceptive behavior in the tail immersion, hot plate and formalin tests and decreased the SOD activity in spinal cord of PND 3 rats. In rats at PND 11 and 90, the neonatal administration of MSG increased mechanical allodynia and nociceptive behavior in the hot plate and formalin tests. The neonatal administration of MSG induced oxidative stress in the hippocampus of rats at PND 11 and in the cerebral cortex at PND 90. These findings demonstrate that nociception and oxidative stress was induced in rats dependent on the time of MSG administration, susceptibility of spinal cord and brain regions and the age of rats.

Asunto(s)

Encéfalo/efectos de los fármacos , Nocicepción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Glutamato de Sodio/toxicidad , Médula Espinal/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Encéfalo/metabolismo , Femenino , Masculino , Nocicepción/fisiología , Estrés Oxidativo/fisiología , Dimensión del Dolor/métodos , Ratas , Médula Espinal/metabolismo

RESUMEN

Appropriate treatment of pain requires analgesics and anti-inflammatory drugs generally associated with undesirable side effects and not fully effective in a significant proportion of patients. Organoselenium compounds elicit a plenty of pharmacological effects in different animal models. Among these compounds, the 2,2`-dipyridyl diselenide (DPD) has a potent antioxidant effect and low toxicity. In this way, the aim of this study was to investigate the possible DPD antinociceptive effect and its mechanism of action, as well as the safety of the compound. Female Swiss mice were treated with vehicle or DPD (0.01-50 mg/kg) intragastrically. Dose-response curve and time-course of the antinociceptive effect of DPD were performed on formalin and tail immersion tests. Morphine (2.5 mg/kg, subcutaneous, 15 min earlier) was used as a positive control in behavioral tests. The results showed that DPD presents a rapid antinociceptive effect in low doses, without changing the spontaneous locomotor activity and parameters of toxicity in mice. The DPD antinociceptive effect was also confirmed in male Swiss mice in both formalin and tail immersion tests. In addition, DPD reduced the paw edema induced by 2.5% formalin and ear edema induced by 2.5% croton oil. l-arginine (600 mg/kg, intraperitoneally) reduced the DPD antinociceptive effect in the first phase of the formalin test. Moreover, DPD attenuated the increase in iNOS, NF-κB and JNK phosphorylation in the spinal cord of mice injected with formalin. These results showed that DPD exerts peripheral and central nociceptive actions associated with anti-inflammatory effect and this organoselenium compound could be an interesting alternative therapy for pain treatment.

Asunto(s)

2,2'-Dipiridil/farmacología , Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Compuestos de Organoselenio/farmacología , Médula Espinal/efectos de los fármacos , 2,2'-Dipiridil/administración & dosificación , 2,2'-Dipiridil/química , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Formaldehído , Masculino , Ratones , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/química , Fosforilación/efectos de los fármacos , Médula Espinal/metabolismo

RESUMEN

The present study aimed to investigate the m-trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] effects on prefrontal cortical MOR and KOR protein levels and phenotype induced by repeated forced swim stress (FSS) in mice. Adult Swiss mice were subjected to repeated FSS sessions, and after that, they performed the spontaneous locomotor/exploratory activity, tail suspension, and splash tests. (m-CF3-PhSe)2 (0.1 to 5 mg/kg) was administered to mice 30 min before the first FSS session and 30 min before the subsequent repeated FSS. (m-CF3-PhSe)2 abolished the phenotype induced by repeated FSS in mice. In addition, a single FSS session increased µ but reduced δ-opioid receptor contents, without changing the κ content. Mice subjected to repeated FSS had an increase in the µ content when compared to those of naïve group or subjected to single FSS. Repeated FSS induced an increase of δ-opioid receptor content compared to those mice subjected to single FSS. However, the δ-opioid receptor contents were lower than those found in the naïve group. The mice subjected to repeated FSS showed an increase in the κ-opioid receptor content when compared to that of the naïve mice. (m-CF3-PhSe)2 regulated the protein contents of µ and κ receptors in mice subjected to repeated FSS. These findings demonstrate that (m-CF3-PhSe)2 was effective to abolish the phenotype induced by FSS, which was accompanied by changes in the contents of cortical µ- and κ-opioid receptors.

Asunto(s)

Compuestos de Organosilicio/uso terapéutico , Corteza Prefrontal/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Natación , Animales , Conducta Animal , Depresión/complicaciones , Depresión/tratamiento farmacológico , Depresión/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Compuestos de Organosilicio/farmacología , Fenotipo , Corteza Prefrontal/efectos de los fármacos , Estrés Psicológico/complicaciones

RESUMEN

Depressive symptoms precipitated by stress are prevalent in population. In experimental models of social stress, endogenous opioids mediate different aspects of defensive and submissive behaviors. The present study investigated the opioid receptors, mitogen-activated protein kinase (MAPKs) and protein kinase B (Akt) contribution to m-trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] effects on social avoidance induced by social defeat stress (SDS). Adult Swiss mice were subjected to SDS and treated with (m-CF3-PhSe)2 (5 to 25mg/kg) for 7days. After that, the mice performed locomotor and social avoidance tests. The opioid receptors, MAPKs and Akt protein contents were determined in the prefrontal cortical samples of mice. Firstly, the mice were segregated in susceptible or resilient subpopulation based on their social avoidance induced by stress. (m-CF3-PhSe)2 (25mg/kg) was effective against the stress-induced social avoidance and improved social interaction behavior in mice. SDS increased the µ and κ protein contents but reduced those of δ opioid receptors in susceptible mice. Resilient and (m-CF3-PhSe)2-treated mice had no alteration in the levels of opioid receptors. Moreover, (m-CF3-PhSe)2 was effective against the increase of c-Jun N-terminal kinase (JNK) and the decrease of Akt phosphorylation protein contents induced by SDS in susceptible mice. The protein content of extracellular signal-regulated kinase (ERK) phosphorylation was reduced in both susceptible and resilient mice, whereas p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation was increased only in resilient mice. (m-CF3-PhSe)2 was partially effective against the pERK decrease and ineffective against the increase in p38 MAPK phosphorylation in mice subjected to SDS. These results suggest that the modulation of protein contents of opioid receptors, JNK and Akt phosphorylation is associated with resilience to SDS promoted by (m-CF3-PhSe)2 in mice.

Asunto(s)

Compuestos de Organosilicio/farmacología , Psicotrópicos/farmacología , Resiliencia Psicológica/efectos de los fármacos , Conducta Social , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptores Opioides/metabolismo

RESUMEN

Parkinson's disease (PD) is a dopaminergic neurodegenerative disorder, which presents motor and non-motor symptoms. 7-Fluoro-1,3-diphenylisoquinoline (FDPI) is an isoquinoline compound with antioxidant and antidepressant properties. This study investigated whether FDPI reverses motor and non-motor symptoms in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It was also assessed the anti-inflammatory mechanisms in FDPI pharmacological action. C57Bl/6 male adult mice received four MPTP (20mg/kg, intraperitoneal) or saline (vehicle) injections to induce an acute PD model. FDPI (10mg/kg, intragastric) was daily administered to mice from the 2nd to 9th day after the induction and mice performed the behavioral tests on the 8th and 9th days. Striatum samples were collected for biochemical and molecular analyses. The results of the rotarod and challenging beam tests demonstrated that the administration of FDPI attenuated the impairments in balance and coordination of mice induced by MPTP. The FDPI reversed the short-term memory deficit and depressive-like behavior induced by MPTP in mice. FDPI attenuated the reduction in the striatal tyrosine hydroxylase levels, and it reversed the increase in the cyclooxygenase-2 levels and myeloperoxidase activity caused by MPTP in mice. Therefore, FDPI reversed motor and non-motor symptoms induced by an acute PD model and its restorative effects seem to be mediated by an anti-inflammatory action associated with a modulation of the striatal cyclooxygenase-2 levels and myeloperoxidase activity.

Asunto(s)

1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antiparkinsonianos/farmacología , Isoquinolinas/farmacología , Actividad Motora/efectos de los fármacos , Neostriado/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/metabolismo , Neostriado/fisiopatología , Reconocimiento en Psicología/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo