Ivabradine possesses anticonvulsant and neuroprotective action in mice.

We analyzed whether ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, clinically used for angina and arrhythmia, had anticonvulsant, antioxidant and neuroprotective properties against classical seizure models. Potential molecular targets to IVA anticonvulsant effects were evaluated by molecular docking. Mice were treated with IVA (1, 10 or 20 mg/kg, IP) for 3 days, and 30 min after the last administration were injected with pentylenetetrazole (PTZ - 85 mg/kg, IP), pilocarpine (PILO 400 mg/kg, SC), picrotoxin (PICRO 10 mg/kg, IP). The following measures were performed: presence of seizures, latency for the first seizure, latency for death, percentage of survival. Antioxidant activity was investigated by determination of lipid peroxidation (MDA), reduced glutathione (GSH) and nitrite levels in the prefrontal cortex (PFC), hippocampus and striatum (ST). Immunohistochemistry analysis for cleaved caspase-3, a pro-apoptotic and degenerative marker, in hippocampal subregions namely cornu ammonis (CA)1, CA3 and dentate gyrus (DG), were also performed. IVA attenuated PTZ- and PICRO-induced seizures while presented an antioxidant effect in all brain areas studied. IVA markedly reduced cleaved caspase-3 expression in the CA1 and DG region of PICRO- and PTZ-treated mice, respectively. Molecular docking demonstrated that IVA has high energetic affinity and binding compatibility for GABAA receptor without causing channel obstruction. However, no reproducibility in the binding of IVA to N-methyl-d-aspartate (NMDA) receptor was detected. In conclusion, IVA has anticonvulsant, antioxidant and neuroprotective effects against PTZ- and PICRO-induced seizures. Also, a high affinity of IVA to GABAA receptor was predicted, representing a potential underlying mechanism to these observable effects.

Effects of agomelatine on oxidative stress in the brain of mice after chemically induced seizures.

Agomelatine is a novel antidepressant drug with melatonin receptor agonist and 5-HT(2C) receptor antagonist properties. We analyzed whether agomelatine has antioxidant properties. Antioxidant activity of agomelatine (25, 50, or 75 mg/kg, i.p.) or melatonin (50 mg/kg) was investigated by measuring lipid peroxidation levels, nitrite content, and catalase activities in the prefrontal cortex, striatum, and hippocampus of Swiss mice pentylenetetrazole (PTZ) (85 mg/kg, i.p.), pilocarpine (400 mg/kg, i.p.), picrotoxin (PTX) (7 mg/kg, i.p.), or strychnine (75 mg/kg, i.p.) induced seizure models. In the pilocarpine-induced seizure model, all dosages of agomelatine or melatonin showed a significant decrease in TBARS levels and nitrite content in all brain areas when compared to controls. In the strychnine-induced seizure model, all dosages of agomelatine and melatonin decreased TBARS levels in all brain areas, and agomelatine at low doses (25 or 50 mg/kg) and melatonin decreased nitrite contents, but only agomelatine at 25 or 50 mg/kg showed a significant increase in catalase activity in three brain areas when compared to controls. Neither melatonin nor agomelatine at any dose have shown no antioxidant effects on parameters of oxidative stress produced by PTX- or PTZ-induced seizure models when compared to controls. Our results suggest that agomelatine has antioxidant activity as shown in strychnine- or pilocarpine-induced seizure models.

Monocrotaline: histological damage and oxidant activity in brain areas of mice.

This work was designed to study MCT effect in histopathological analysis of hippocampus (HC) and parahippocampal cortex (PHC) and in oxidative stress (OS) parameters in brain areas such as hippocampus (HC), prefrontal cortex (PFC), and striatum (ST). Swiss mice (25-30 g) were administered a single i.p. dose of MCT (5, 50, or 100 mg/kg) or 4% Tween 80 in saline (control group). After 30 minutes, the animals were sacrificed by decapitation and the brain areas (HC, PHC, PFC, or ST) were removed for histopathological analysis or dissected and homogenized for measurement of OS parameters (lipid peroxidation, nitrite, and catalase) by spectrophotometry. Histological evaluation of brain structures of rats treated with MCT (50 and 100 mg/kg) revealed lesions in the hippocampus and parahippocampal cortex compared to control. Lipid peroxidation was evident in all brain areas after administration of MCT. Nitrite/nitrate content decreased in all doses administered in HC, PFC, and ST. Catalase activity was increased in the MCT group only in HC. In conclusion, monocrotaline caused cell lesions in the hippocampus and parahippocampal cortex regions and produced oxidative stress in the HC, PFC, and ST in mice. These findings may contribute to the neurological effects associated with this compound.

Oxidative stress and epilepsy: literature review.

BACKGROUNDS: The production of free radicals has a role in the regulation of biological function, cellular damage, and the pathogenesis of central nervous system conditions. Epilepsy is a highly prevalent serious brain disorder, and oxidative stress is regarded as a possible mechanism involved in epileptogenesis. Experimental studies suggest that oxidative stress is a contributing factor to the onset and evolution of epilepsy. OBJECTIVE: A review was conducted to investigate the link between oxidative stress and seizures, and oxidative stress and age as risk factors for epilepsy. The role of oxidative stress in seizure induction and propagation is also discussed. RESULTS/CONCLUSIONS: Oxidative stress and mitochondrial dysfunction are involved in neuronal death and seizures. There is evidence that suggests that antioxidant therapy may reduce lesions induced by oxidative free radicals in some animal seizure models. Studies have demonstrated that mitochondrial dysfunction is associated with chronic oxidative stress and may have an essential role in the epileptogenesis process; however, few studies have shown an established link between oxidative stress, seizures, and age.

Anticonvulsant effects of agomelatine in mice.

Agomelatine is a potent MT1 and MT2 melatonin receptor agonist and a 5-HT2C serotonin receptor antagonist. We analyzed whether agomelatine has anticonvulsant properties. The anticonvulsant activity of agomelatine (25, 50 or 75 mg/kg, i.p.) was evaluated in mouse models of pentylenetetrazole (PTZ-85 mg/kg, i.p.), pilocarpine (400mg/kg, i.p.), picrotoxin (7 mg/kg, i.p.), strychnine (75 mg/kg, i.p.) or electroshock-induced convulsions. In the PTZ-induced seizure model, agomelatine (at 25 or 50mg/kg) showed a significant increase in latency to convulsion, and agomelatine (at 50 or 75 mg/kg) also increased significantly time until death. In the pilocarpine-induced seizure model, only agomelatine in high doses (75 mg/kg) showed a significant increase in latency to convulsions and in time until death. In the strychnine-, electroshock- and picrotoxin-induced seizure models, agomelatine caused no significant alterations in latency to convulsions and in time until death when compared to controls. Our results suggest that agomelatine has anticonvulsant activity shown in PTZ- or pilocarpine-induced seizure models.

Anticonvulsant action of Calotropis procera latex proteins.

Calotropis procera (Ait.) R.Br. is a laticiferous plant belonging to the Apocynaceae family. C. procera latex proteins were evaluated with respect to anticonvulsant and sedative activity in mouse models of pentylenetetrazol (PTZ)-, pilocarpine-, and strychnine-induced convulsions or turning behavior and pentobarbital-induced sleep. In the strychnine- and pilocarpine-induced seizure models, C. procera latex proteins caused no significant alterations in latencies to convulsions and death, as compared with controls. In the PTZ-induced seizure model, administration of C. procera latex proteins in high doses (50 or 100mg/kg) and diazepam caused significant increases in latencies to convulsions and death. C. procera latex proteins (50 or 100mg/kg) and 2mg/kg diazepam caused a decrease in sleep latency and an increase in sleep time compared with the control group and groups treated with 5 or 10mg/kg. Our results suggest that C. procera latex proteins have a central nervous system-depressant activity as reflected in their potentiation of pentobarbital-induced sleeping time and their anticonvulsant action in the PTZ-induced seizure model.

Esquizofrenia: uma doença inflamatória?: [revisão] / Schizophrenia: an inflammatory disease?: [review]

OBJETIVO: Neste estudo, o objetivo foi revisar o papel de um possível processo inflamatório na gênese da esquizofrenia. MÉTODO: Foram selecionados os trabalhos publicados em revistas indexadas nas bases de dados Lilacs e MedLine, sob os unitermos "esquizofrenia", "inflamação" e "estresse oxidativo", nos últimos 10 anos até dezembro de 2009, nos idiomas inglês e português. Foram excluídos os artigos que tratavam de aspectos fisiopatológicos da doença fora do interesse da psiquiatria. RESULTADOS: Sessenta e um artigos foram selecionados. Doze abordavam o envolvimento do estresse oxidativo na esquizofrenia, nove tratavam de alterações no sistema imunológico de pacientes esquizofrênicos, dezesseis da infecção pré-natal como desencadeador da doença e sete mostravam a ação antioxidante e anti-inflamatória de fármacos antipsicóticos. CONCLUSÃO: Os estudos enfatizam o envolvimento do sistema imunológico (isto é, interleucinas e ação anti-inflamatória dos antipsicóticos), das infecções, do estresse oxidativo e da função mitocondrial na fisiopatologia da esquizofrenia. Portanto, esses novos achados são importantes para a melhor compreensão e, consequentemente, a elaboração de terapias mais específicas e eficazes no combate dessa doença mental.

OBJECTIVE: We aimed at reviewing about the influence of the inflammatory process in the genesis of schizophrenia. METHOD: A search for papers published in Lilacs and MedLine databases during the last 10 years until December 2009 was made using the terms "schizophrenia", "inflammation" and "oxidative stress". The papers concerning other pathophysiologic aspects of schizophrenia not exclusively related to psychiatry were excluded. RESULTS: Sixty-one articles were selected: twelve were involved the role of oxidative stress, nine dealt with changes in the immune system, and sixteen referred to prenatal infection as the trigger of schizophrenia. Seven articles showed the anti-inflammatory and antioxidant action of antipsychotic drugs. CONCLUSION: The studies emphasized the importance of the mitochondrial function, oxidative stress, immunological system (interleukin, anti-inflammatory action of the antipsychotics) and infections in the pathophysiology of schizophrenia. These findings are important for a better understanding and consequently the development of more specific and effective therapies for schizophrenia.

[Assessment instruments for a Health-Related Quality of Life in diabetes mellitus]. / Instrumentos de avaliação de qualidade de vida relacionada à saúde no diabetes melito.

The assessment of Health-Related Quality of Life (HRQoL) has been increasingly used to measure the overall impact of diseases in people's life. Diabetes mellitus (DM) is a chronic disease associated with high morbidity, mortality, and HRQoL impairment in patients. In longitudinal studies, the psychosocial impact of DM predicts mortality. The objective of this review is to describe and to analyze the main instruments used for the HRQoL evaluation in patients with DM. Generic instruments such, as the Quality of Well-Being Scale (QWB), Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), EuroQol (EQ-5D) and specific instruments as the Diabetes Care Profile (DCP), Diabetes Quality of Life Measure (DQOL), Diabetes Impact Measurement Scales (DIMS), Appraisal of Diabetes Scale (ADS), Audit of Diabetes-Dependent Quality of Life (ADDQoL), Diabetes Health Profile (DHP-1 and DHP-18), Questionnaire on Stress in Patients with Diabetes-Revised (QSD-R), Well-Being Enquiry goes Diabetics (WED), Diabetes-Specific Quality-of-life Scale (DSQOLS), Diabetes 39 (D-39) Problems Areas in Diabetes (PAID) were analyzed. PAID is the only translated and validated instrument available in Brazil. The generic and specific instruments have their stregths and shortcomings for evaluation of HRQL in patients with DM. The combined use of both generic (such as the SF-36) and specific (such as the PAID) appears to be a consistent way to evaluate HRQoL as a construct in Brazilian patients with DM. The present article reviews a variety of instruments and emphasizes the urgent need for validation studies of such instruments to be used in Brazilian subjects with DM.

Instrumentos de avaliação de qualidade de vida relacionada à saúde no diabetes melito: [revisão] / Assessment instruments for a Health-Related Quality of Life in diabetes mellitus: [review]

A avaliação da qualidade de vida (QV) vem se tornando cada vez mais utilizada para medir o impacto geral de doenças na vida dos indivíduos. O diabetes melito (DM) é uma doença crônica associada com morbimortalidade elevada e prejuízo na QV. Em estudos longitudinais, o impacto psicossocial da DM prediz a mortalidade nessa doença. Esta revisão busca descrever e analisar os principais instrumentos de avaliação da QV em pacientes com DM. Foram analisados instrumentos genéricos, como Quality of Well-Being Scale (QWB), The Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) e EuroQol (EQ-5D), e instrumentos específicos, como Diabetes Care Profile (DCP), Diabetes Quality of Life Measure (DQOL), Diabetes Impact Measurement Scales (DIMS), Appraisal of Diabetes Scale (ADS), Audit of Diabetes-Dependent Quality of Life (ADDQoL), Diabetes Health Profile (DHP-1 e DHP-18), Questionnaire on Stress in Patients with Diabetes-Revised (QSD-R), Well-Being Enquiry for Diabetics (WED), Diabetes-Specific Quality-of-life Scale (DSQOLS), Diabetes 39 (D-39) e Problems Areas in Diabetes (PAID). O PAID é o único instrumento traduzido e validado para uso no Brasil. Tanto os instrumentos genéricos quanto os específicos têm vantagens e desvantagens na aferição da QV de pacientes com DM. O uso combinado de instrumentos genéricos (como o SF-36) e específicos (como o PAID) parece ser uma forma consistente de avaliação da QV em pacientes diabéticos no Brasil. O presente artigo revisa os vários instrumentos e enfatiza a necessidade urgente de estudos para validação desses instrumentos em pacientes diabéticos brasileiros.

The assessment of Health-Related Quality of Life (HRQoL) has been increasingly used to measure the overall impact of diseases in people's life. Diabetes mellitus (DM) is a chronic disease associated with high morbidity, mortality, and HRQoL impairment in patients. In longitudinal studies, the psychosocial impact of DM predicts mortality. The objective of this review is to describe and to analyze the main instruments used for the HRQoL evaluation in patients with DM. Generic instruments such, as the Quality of Well-Being Scale (QWB), Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), EuroQol (EQ-5D) and specific instruments as the Diabetes Care Profile (DCP), Diabetes Quality of Life Measure (DQOL), Diabetes Impact Measurement Scales (DIMS), Appraisal of Diabetes Scale (ADS), Audit of Diabetes-Dependent Quality of Life (ADDQoL), Diabetes Health Profile (DHP-1 and DHP-18), Questionnaire on Stress in Patients with Diabetes-Revised (QSD-R), Well-Being Enquiry goes Diabetics (WED), Diabetes-Specific Quality-of-life Scale (DSQOLS), Diabetes 39 (D-39) Problems Areas in Diabetes (PAID) were analyzed. PAID is the only translated and validated instrument available in Brazil. The generic and specific instruments have their stregths and shortcomings for evaluation of HRQL in patients with DM. The combined use of both generic (such as the SF-36) and specific (such as the PAID) appears to be a consistent way to evaluate HRQoL as a construct in Brazilian patients with DM. The present article reviews a variety of instruments and emphasizes the urgent need for validation studies of such instruments to be used in Brazilian subjects with DM.