RESUMEN
This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1 mg/kg), scopolamine plus inosine (50 mg/kg), and scopolamine plus inosine (100 mg/kg). Inosine was pre-administered for 7 days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24 hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer's disease.
Asunto(s)
Disfunción Cognitiva , Consolidación de la Memoria , Acetilcolinesterasa/metabolismo , Animales , Colinérgicos/efectos adversos , Inosina/efectos adversos , Bombas Iónicas/farmacología , Bombas Iónicas/uso terapéutico , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Oxidación-Reducción , Estrés Oxidativo , Ratas , Ratas Wistar , Escopolamina/farmacologíaRESUMEN
Bipolar disorder is characterized by episodes of depression and mania, and oxidative stress has been associated with the observed neurochemical changes in this disease. We evaluated the effects of gallic acid on hyperlocomotion, acetylcholinesterase activity, and oxidative stress in an animal model of ketamine-induced mania. Rats were pretreated orally with vehicle, gallic acid (50 or 100 mg/kg), or lithium (45 mg/kg twice a day) for 14 days. Between days 8 and 14, the animals also received ketamine (25 mg/kg) or saline daily. On the 15th day, hyperlocomotion was assessed, following which the animals were euthanized, and brains were collected. Results showed that ketamine-induced hyperlocomotion and caused oxidative damage by increasing reactive oxygen species levels, lipid peroxidation, and nitrite levels, and decreasing the total thiol content and the activities of catalase, superoxide dismutase, and glutathione peroxidase in the brain. Pretreatment with gallic acid and lithium prevented hyperlocomotion and brain oxidative damage. Further, ketamine increased the acetylcholinesterase activity in the hippocampus and striatum, whereas gallic acid and lithium ameliorated this alteration. Thus, gallic acid may provide effective protection against manic-like behavior by reducing oxidative stress and preventing cholinergic signaling dysfunction in the brain regions involved in emotion regulation.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Ácido Gálico/uso terapéutico , Hipocampo/efectos de los fármacos , Litio/uso terapéutico , Manía/tratamiento farmacológico , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Ácido Gálico/farmacología , Hipocampo/metabolismo , Litio/farmacología , Masculino , Manía/metabolismo , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Autism is a neuropathology characterized by behavioral disorders. Considering that oxidative stress is involved in the pathophysiology of this disease, we evaluated the effects of quercetin, a flavonoid with antioxidant and neuroprotective properties, in an experimental model of autism induced by valproic acid (VPA). Twelve pregnant female rats were divided into four groups (control, quercetin, VPA, and VPA+quercetin). Quercetin (50 mg/kg) was administered orally to the animals from gestational days 6.5 to 18.5, and VPA (800 mg/kg) was administered orally in a single dosage on gestational day 12.5. Behavioral tests such as open field, social interaction, and tail flick nociceptive assays were performed on pups between 30 and 40 days old, after which the animals were euthanized. Cerebral cortex, hippocampus, striatum, and cerebellum were collected for evaluation of oxidative stress parameters. The pups exposed to VPA during the gestational period showed reduced weight gain, increased latency in the open field and tail flick tests, reduced time of social interaction, accompanied by changes in oxidative stress parameters mainly in the hippocampus and striatum. Prenatal treatment with quercetin prevented the behavioral changes and damage caused by oxidative stress, possibly due to its antioxidant action. Our findings demonstrated that quercetin has neuroprotective effects in an animal model of autism, suggesting that this natural molecule could be an important therapeutic agent for treatment of autism spectrum disorders (ASDs).
Asunto(s)
Trastorno Autístico/prevención & control , Trastorno Autístico/psicología , Química Encefálica , Porfobilinógeno Sintasa/metabolismo , Quercetina/uso terapéutico , Animales , Anticonvulsivantes , Trastorno Autístico/inducido químicamente , Femenino , Actividad Motora , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo , Dimensión del Dolor , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar , Interacción Social , Ácido Valproico , Aumento de PesoRESUMEN
Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A1 and A2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A1 and A2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.
Asunto(s)
Hipercinesia/inducido químicamente , Hipercinesia/prevención & control , Inosina/administración & dosificación , Ketamina/administración & dosificación , Locomoción/efectos de los fármacos , Manía/inducido químicamente , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipercinesia/metabolismo , Masculino , Manía/metabolismo , Ratas Wistar , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismoRESUMEN
The aim of this study was to investigate the effect of the chronic administration of methionine (Met) and/or its metabolite, methionine sulfoxide (MetO), on the behavior and neurochemical parameters of young rats. Rats were treated with saline (control), Met (0.2-0.4 g/kg), MetO (0.05-0.1 g/kg), and/or a combination of Met + MetO, subcutaneously twice a day from postnatal day 6 (P6) to P28. The results showed that Met, MetO, and Met + MetO impaired short-term and spatial memories (P < 0.05), reduced rearing and grooming (P < 0.05), but did not alter locomotor activity (P > 0.05). Acetylcholinesterase activity was increased in the cerebral cortex, hippocampus, and striatum following Met and/or MetO (P < 0.05) treatment, while Na+, K+-ATPase activity was reduced in the hippocampus (P < 0.05). There was an increase in the level of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex in Met-, MetO-, and Met + MetO-treated rats (P < 0.05). Met and/or MetO treatment reduced superoxide dismutase, catalase, and glutathione peroxidase activity, total thiol content, and nitrite levels, and increased reactive oxygen species and TBARS levels in the hippocampus and striatum (P < 0.05). Hippocampal brain-derived neurotrophic factor was reduced by MetO and Met + MetO compared with the control group. The number of NeuN-positive cells was decreased in the CA3 in Met + MetO group and in the dentate gyrus in the Met, MetO, and Met + MetO groups compared to control group (P < 0.05). Taken together, these findings further increase our understanding of changes in the brain in hypermethioninemia by elucidating behavioral alterations, biological mechanisms, and the vulnerability of brain function to high concentrations of Met and MetO.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Glicina N-Metiltransferasa/deficiencia , Hipocampo/patología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Metionina/análogos & derivados , Especies Reactivas de Oxígeno/metabolismo , Acetilcolinesterasa/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/inducido químicamente , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Animales , Catalasa/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Femenino , Glutatión Peroxidasa/deficiencia , Glicina N-Metiltransferasa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/metabolismo , Memoria a Corto Plazo/efectos de los fármacos , Metionina/metabolismo , Metionina/toxicidad , Ratas , Ratas Wistar , Memoria Espacial/efectos de los fármacos , Superóxido Dismutasa/deficiencia , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
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/metabolismoRESUMEN
PURPOSE: Down syndrome (DS) is caused by the triplication of chromosome 21. Studies have demonstrated platelets abnormalities and oxidative stress in DS subjects. The enzymes NTPDase, 5'-nucleotidase and adenosine deaminase (ADA) represent an important therapeutic target since they interfere in the extracellular nucleotide pool altering platelet functions. In this study, we evaluated the ectonucleotidases activities and oxidative stress parameters in samples of DS and healthy individuals. METHODS AND RESULTS: The population consisted of 28 subjects with DS and 28 healthy subjects as a control group. Blood was obtained from each subject and used for platelet and serum preparation. NTPDase activity using ATP as substrate was increased in platelets of DS patients in relation to the control group; however, no alterations were observed in the ADP hydrolysis. A decrease in the 5'-nucleotidase activity and an increase in the ADA activity was observed in platelet of DS subjects when compared to healthy individuals (P<0.05). The lipid peroxidation and total thiol content was decreased in serum of DS individuals. Furthermore, superoxide dismutase and catalase activities were increased in whole blood of this group (P<0.05). CONCLUSION: Alterations in the ectonucleotidase activities in platelets as well as changes in the oxidative stress parameters may contribute to the clinical features of DS.