RESUMEN
Typical antipsychotics, which are commonly used to treat schizophrenia, cause motor disorders such as tardive dyskinesia (TD) in humans and orofacial dyskinesia (OD) in rodents. The disease mechanisms as well as treatment effectiveness are still unknown. In this study, we investigated the effect of resveratrol, a polyphenol with neuroprotective properties, on behavioral changes induced by chronic treatment with fluphenazine in rats and the possible relationship between monoamine oxidase (MAO) activity and vacuous chewing movements (VCMs). Rats were treated for 18 weeks with fluphenazine enantate [25 mg/kg, intramuscularly (i.m.), every 21 days] and/or resveratrol (20 mg/kg, offered daily in drinking water). Next, body weight gain, behavioral parameters (VCMs and open field tests-locomotor and rearing activity), and MAO activity were evaluated. Fluphenazine treatment reduced body weight gain, number of crossings and rearings, and the co-treatment with resveratrol did not affect these alterations. Fluphenazine increased the prevalence and intensity of VCMs and the co-treatment with resveratrol reduced the VCMs. Furthermore, a negative correlation was found between the number of VCMs and MAO-B activity in the striatum of rats. Our data suggest that resveratrol could be promissory to decrease OD. Moreover, MAO-B activity in the striatum seems to be related to VCMs intensity.
Asunto(s)
Antioxidantes/uso terapéutico , Antipsicóticos/toxicidad , Discinesias/prevención & control , Flufenazina/toxicidad , Actividad Motora/efectos de los fármacos , Estilbenos/uso terapéutico , Animales , Antioxidantes/farmacología , Antipsicóticos/administración & dosificación , Esquema de Medicación , Discinesias/psicología , Flufenazina/administración & dosificación , Masculino , Masticación/efectos de los fármacos , Masticación/fisiología , Actividad Motora/fisiología , Ratas , Ratas Wistar , Resveratrol , Estilbenos/farmacologíaRESUMEN
The study evaluated whether a diet containing diphenyl diselenide (PhSe)2, a synthetic antioxidant, could reduce the biochemical alterations induced by chronic consumption of highly enriched fructose diet and/or hydrochlorothiazide (HCTZ). Rats were fed a control diet (CT) or a high fructose diet (HFD), supplemented with or not HCTZ (4.0g/kg) and/or (PhSe)2 (3ppm) for 18weeks. HFD intake increased significantly plasma glucose, fructosamine, triglycerides and cholesterol levels. (PhSe)2 supplementation significantly reduced triglycerides and cholesterol but could not restore them to control levels. The combination of HFD and HCTZ significantly altered plasma glucose, fructosamine, triglycerides and cholesterol levels which were not restore by (PhSe)2 supplementation. Lipid peroxidation, protein carbonyl formation, vitamin C level and catalase activity decreased after HFD, HCTZ or HFD plus HCTZ ingestion. Remarkably (PhSe)2 supplementation restored the oxidative stress parameters. HCTZ decreased renal superoxide dismutase (SOD) activity, which was restored to control levels by (PhSe)2. Furthermore, the association of HFD and HCTZ decreased plasma potassium levels and aggravated HCTZ-induced hypomagnesemia and hypertriglyceridemia. Here we provided evidence of the involvement of oxidative stress and metabolic disorders in a rat model of HFD associated or not with HTCZ. (PhSe)2 supplementation reduced the oxidative stress and this compound should be considered for the treatment of biochemical disturbances and oxidative stress in other animal models of metabolic disorders.
Asunto(s)
Antioxidantes/farmacología , Derivados del Benceno/farmacología , Dieta , Suplementos Dietéticos , Fructosa/metabolismo , Hidroclorotiazida/metabolismo , Compuestos de Organoselenio/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Catalasa/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Masculino , Ratas , Ratas WistarRESUMEN
Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 µM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 µM, whereas 2(3-(phenylhydrazono)butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 µM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning.
Asunto(s)
Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/farmacología , Insecticidas/toxicidad , Cloruro de Obidoxima/farmacología , Compuestos Organotiofosforados/toxicidad , Compuestos de Pralidoxima/farmacología , Acetilcolinesterasa/sangre , Animales , Butirilcolinesterasa/sangre , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Humanos , Masculino , Ratas , Ratas WistarRESUMEN
Organophosphates (OPs), which are widely used as pesticides, are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death. The classical treatment for OP poisoning is administration of oximes, but these compounds are ineffective in some cases. Here we determined whether the new compound isatin-3-N(4)-benzilthiosemicarbazone (IBTC), which in our previous study proved to be an antioxidant and antiatherogenic molecule, could protect and reactivate AChE and BChE. Toxicity of IBTC after subcutaneous injection in mice was measured using assays for oxidized diclorofluoresceine (DCF), thiobarbituric acid reactive substances (TBARS), non-protein thiol (NPSH) levels, and catalase (CAT), sodium potassium (Na(+)/K(+)) ATPase, delta-aminolevulinic acid dehydratase (ALA-D), and glutathione peroxidases (GPx) enzyme activities. The cytotoxicity was evaluated and the enzymatic activity of cholinesterase was measured in human blood samples. Molecular docking was used to predict the mechanism of IBTC interactions with the AChE active site. We found that IBTC did not increase the amount of DCF-RS or TBARS, did not reduce NPSH levels, and did not increase CAT, (Na(+)/K(+)) ATPase, ALA-D, or GPx activities. IBTC protected and reactivated both AChE and BChE activities. Molecular docking predicted that IBTC is positioned at the peripheral anionic site and in the acyl binding pocket of AChE and can interact with methamidophos, releasing the enzyme's active site. Our results suggest that IBTC, besides being an antioxidant and a promising antiatherogenic agent, is a non-toxic molecule for methamidophos poisoning treatment.
Asunto(s)
Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/farmacología , Insecticidas/toxicidad , Isatina/análogos & derivados , Isatina/farmacología , Compuestos Organotiofosforados/toxicidad , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colinesterasas/metabolismo , Humanos , Linfocitos , Masculino , Ratones , Simulación del Acoplamiento Molecular , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
The antioxidant properties of organoselenium compounds have been extensively investigated because oxidative stress is a hallmark of a variety of chronic human diseases. Here, we reported the influence of substituent groups in the antioxidant activity of ß-selenoamines. We have investigated whether they exhibited glutathione peroxidase-like (GPx-like) activity and whether they could be substrate of thioredoxin reductase (TrxR). In the DPPH assay, the ß-selenium amines did not exhibit antioxidant activity. However, the ß-selenium amines with p-methoxy and tosyl groups prevented the lipid peroxidation. The ß-selenium amine compound with p-methoxy substituent group exhibited thiol-peroxidase-like activity (GPx-like activity) and was reduced by the hepatic TrxR. These results contribute to understand the influence of structural alteration of non-conventional selenium compounds as synthetic mimetic of antioxidant enzymes of mammalian organisms.
Asunto(s)
Depuradores de Radicales Libres/química , Compuestos de Organoselenio/química , Peroxidasas/química , Animales , Compuestos de Bifenilo/química , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catálisis , Depuradores de Radicales Libres/farmacología , Radicales Libres/química , Peroxidación de Lípido , Hígado/enzimología , Masculino , NADP/química , Compuestos de Organoselenio/farmacología , Oxidación-Reducción , Peroxidasas/farmacología , Picratos/química , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Reductasa de Tiorredoxina-Disulfuro/química , Reductasa de Tiorredoxina-Disulfuro/aislamiento & purificaciónRESUMEN
Valeriana officinalis L. (Valerian) is widely used as a traditional medicine to improve the quality of sleep. Although V. officinalis have been well documented as promising pharmacological agent; the exact mechanisms by which this plant act is still unknown. Limited literature data have indicated that V. officinalis extracts can exhibit antioxidant properties against iron in hippocampal neurons in vitro. However, there is no data available about the possible antioxidant effect of V. officinalis against other pro-oxidants in brain. In the present study, the protective effect of V. officinalis on lipid peroxidation (LPO) induced by different pro-oxidant agents with neuropathological importance was examined. Ethanolic extract of valerian (0-60 microg/ml) was tested against quinolinic acid (QA); 3-nitropropionic acid; sodium nitroprusside; iron sulfate (FeSO4) and Fe2+/EDTA induced LPO in rat brain homogenates. The effect of V. officinalis in deoxyribose degradation and reactive oxygen species (ROS) production was also investigated. In brain homogenates, V. officinalis inhibited thiobarbituric acid reactive substances induced by all pro-oxidants tested in a concentration dependent manner. Similarly, V. officinalis caused a significant decrease on the LPO in cerebral cortex and in deoxyribose degradation. QA-induced ROS production in cortical slices was also significantly reduced by V. officinalis. Our results suggest that V. officinalis extract was effective in modulating LPO induced by different pro-oxidant agents. These data may imply that V. officinalis extract, functioning as antioxidant agent, can be beneficial for reducing insomnia complications linked to oxidative stress.
Asunto(s)
Antioxidantes/farmacología , Neurotoxinas/antagonistas & inhibidores , Neurotoxinas/toxicidad , Valeriana/química , Animales , Química Encefálica/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Desoxirribosa/metabolismo , Ácido Edético/farmacología , Ácido Gálico/farmacología , Peróxidos Lipídicos/metabolismo , Masculino , Nitrocompuestos/antagonistas & inhibidores , Nitrocompuestos/toxicidad , Oxidantes/farmacología , Extractos Vegetales/farmacología , Raíces de Plantas/química , Propionatos/antagonistas & inhibidores , Propionatos/toxicidad , Ácido Quinolínico/antagonistas & inhibidores , Ácido Quinolínico/toxicidad , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
The effect of dietary diphenyl diselenide (1 ppm) on N-nitroso-N-methylurea (NMU)-induced mammary carcinogenesis was examined in female Wistar rats. Beginning at 5 weeks of age, the animals were fed with either control or diphenyl-diselenide-supplied diets until the end of the study (210 days). At 50 days of age, mammary tumor was induced by the administration of three doses of NMU (50 mg/kg body wt, intraperitoneally) once a week for 3 weeks. In experimental trials, latency to tumor onset was extended in rats fed with diet supplemented with diphenyl diselenide (P < 0.05). The incidence and frequency of tumors were significantly small in animals supplemented with diphenyl diselenide. However, the multiplicity of tumors was not altered by dietary diphenyl diselenide. Diphenyl diselenide supplementation also restored superoxide dismutase (SOD) activity and vitamin C levels altered in the NMU group (P < 0.05). Our results suggest that diphenyl diselenide can be considered a chemopreventive agent, even when supplemented at a relatively low concentration.