RESUMEN
The current drug therapy for schizophrenia effectively treats acute psychosis and its recurrence; however, this mental disorder's cognitive and negative symptoms are still poorly controlled. Antipsychotics present important side effects, such as weight gain and extrapyramidal effects. The essential oil of Alpinia zerumbet (EOAZ) leaves presents potential antipsychotic properties that need further preclinical investigation. Here, we determined EAOZ effects in preventing and reversing schizophrenia-like symptoms (positive, negative, and cognitive) induced by ketamine (KET) repeated administration in mice and putative neurobiological mechanisms related to this effect. We conducted the behavioral evaluations of prepulse inhibition of the startle reflex (PPI), social interaction, and working memory (Y-maze task), and verified antioxidant (GSH, nitrite levels), anti-inflammatory [interleukin (IL)-6], and neurotrophic [brain-derived neurotrophic factor (BDNF)] effects of this oil in hippocampal tissue. The atypical antipsychotic olanzapine (OLZ) was used as standard drug therapy. EOAZ, similarly to OLZ, prevented and reversed most KET-induced schizophrenia-like behavioral alterations, i.e., sensorimotor gating deficits and social impairment. EOAZ had a modest effect on the prevention of KET-associated working memory deficit. Compared to OLZ, EOAZ showed a more favorable side effects profile, inducing less cataleptic and weight gain changes. EOAZ efficiently protected the hippocampus against KET-induced oxidative imbalance, IL-6 increments, and BDNF impairment. In conclusion, our data add more mechanistic evidence for the anti-schizophrenia effects of EOAZ, based on its antioxidant, anti-inflammatory, and BDNF up-regulating actions. The absence of significant side effects observed in current antipsychotic drug therapy seems to be an essential benefit of the oil.
Asunto(s)
Alpinia , Antipsicóticos , Aceites Volátiles , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo , Ratones , Aceites Volátiles/farmacología , Aceites Volátiles/uso terapéutico , OlanzapinaRESUMEN
OBJECTIVE:: To evaluate the effects of passive inhalation of cigarette smoke on the respiratory system of guinea pigs. METHODS:: Male guinea pigs were divided into two groups: control and passive smoking, the latter being exposed to the smoke of ten cigarettes for 20 min in the morning, afternoon and evening (30 cigarettes/day) for five days. After that period, inflammatory parameters were studied by quantifying mesenteric mast cell degranulation, as well as oxidative stress, in BAL fluid. In addition, we determined MIP, MEP, and mucociliary transport (in vivo), as well as tracheal contractility response (in vitro). RESULTS:: In comparison with the control group, the passive smoking group showed a significant increase in mast cell degranulation (19.75 ± 3.77% vs. 42.53 ± 0.42%; p < 0.001) and in the levels of reduced glutathione (293.9 ± 19.21 vs. 723.7 ± 67.43 nM/g of tissue; p < 0.05); as well as a significant reduction in mucociliary clearance (p < 0.05), which caused significant changes in pulmonary function (in MIP and MEP; p < 0.05 for both) and airway hyperreactivity. CONCLUSIONS:: Passive inhalation of cigarette smoke caused significant increases in mast cell degranulation and oxidative stress. This inflammatory process seems to influence the decrease in mucociliary transport and to cause changes in pulmonary function, leading to tracheal hyperreactivity. OBJETIVO:: Avaliar os efeitos da inalação passiva da fumaça de cigarro no sistema respiratório de cobaias. MÉTODOS:: Foram utilizadas cobaias machos, divididas em dois grupos: controle e tabagismo passivo, esse último exposto à fumaça de dez cigarros por 20 min pela manhã, tarde e noite (30 cigarros/dia) por 5 dias. Após esse período, parâmetros inflamatórios foram estudados através da contagem de degranulação de mastócitos no mesentério e de estresse oxidativo a partir do LBA. Adicionalmente, foram verificadas PImáx, PEmáx, transporte mucociliar (in vivo) e contratilidade traqueal (in vitro). RESULTADOS:: Na comparação com o grupo controle, o grupo tabagismo passivo apresentou um aumento significativo na degranulação de mastócitos (19,75 ± 3,77% vs. 42,53 ± 0,42%; p < 0,001), nos níveis de glutationa reduzida (293,9 ± 19,21 vs. 723,7 ± 67,43 nM/g de tecido; p < 0,05) e uma redução significativa no transporte mucociliar (p < 0,05), provocando alterações significativas na função pulmonar, tanto na PImáx como na PEmáx (p < 0,05 para ambas), e hiper-reatividade nas vias aéreas. CONCLUSÕES:: A inalação passiva da fumaça de cigarro ocasionou aumentos significativos na degranulação de mastócitos e no estresse oxidativo. Esse processo inflamatório parece ter influenciado a diminuição do transporte mucociliar e causado alterações na função pulmonar, proporcionando um quadro de hiper-reatividade traqueal.
Asunto(s)
Degranulación de la Célula , Inflamación/etiología , Exposición por Inhalación/efectos adversos , Mastocitos/fisiología , Contaminación por Humo de Tabaco/efectos adversos , Animales , Estudios de Evaluación como Asunto , Cobayas , Estudios Longitudinales , Masculino , Modelos Animales , Depuración Mucociliar/fisiología , Contracción Muscular/fisiología , Estrés Oxidativo/fisiologíaRESUMEN
ABSTRACT Objective: To evaluate the effects of passive inhalation of cigarette smoke on the respiratory system of guinea pigs. Methods: Male guinea pigs were divided into two groups: control and passive smoking, the latter being exposed to the smoke of ten cigarettes for 20 min in the morning, afternoon and evening (30 cigarettes/day) for five days. After that period, inflammatory parameters were studied by quantifying mesenteric mast cell degranulation, as well as oxidative stress, in BAL fluid. In addition, we determined MIP, MEP, and mucociliary transport (in vivo), as well as tracheal contractility response (in vitro). Results: In comparison with the control group, the passive smoking group showed a significant increase in mast cell degranulation (19.75 ± 3.77% vs. 42.53 ± 0.42%; p < 0.001) and in the levels of reduced glutathione (293.9 ± 19.21 vs. 723.7 ± 67.43 nM/g of tissue; p < 0.05); as well as a significant reduction in mucociliary clearance (p < 0.05), which caused significant changes in pulmonary function (in MIP and MEP; p < 0.05 for both) and airway hyperreactivity. Conclusions: Passive inhalation of cigarette smoke caused significant increases in mast cell degranulation and oxidative stress. This inflammatory process seems to influence the decrease in mucociliary transport and to cause changes in pulmonary function, leading to tracheal hyperreactivity.
RESUMO Objetivo: Avaliar os efeitos da inalação passiva da fumaça de cigarro no sistema respiratório de cobaias. Métodos: Foram utilizadas cobaias machos, divididas em dois grupos: controle e tabagismo passivo, esse último exposto à fumaça de dez cigarros por 20 min pela manhã, tarde e noite (30 cigarros/dia) por 5 dias. Após esse período, parâmetros inflamatórios foram estudados através da contagem de degranulação de mastócitos no mesentério e de estresse oxidativo a partir do LBA. Adicionalmente, foram verificadas PImáx, PEmáx, transporte mucociliar (in vivo) e contratilidade traqueal (in vitro). Resultados: Na comparação com o grupo controle, o grupo tabagismo passivo apresentou um aumento significativo na degranulação de mastócitos (19,75 ± 3,77% vs. 42,53 ± 0,42%; p < 0,001), nos níveis de glutationa reduzida (293,9 ± 19,21 vs. 723,7 ± 67,43 nM/g de tecido; p < 0,05) e uma redução significativa no transporte mucociliar (p < 0,05), provocando alterações significativas na função pulmonar, tanto na PImáx como na PEmáx (p < 0,05 para ambas), e hiper-reatividade nas vias aéreas. Conclusões: A inalação passiva da fumaça de cigarro ocasionou aumentos significativos na degranulação de mastócitos e no estresse oxidativo. Esse processo inflamatório parece ter influenciado a diminuição do transporte mucociliar e causado alterações na função pulmonar, proporcionando um quadro de hiper-reatividade traqueal.
Asunto(s)
Animales , Masculino , Cobayas , Degranulación de la Célula , Inflamación/etiología , Exposición por Inhalación/efectos adversos , Mastocitos/fisiología , Contaminación por Humo de Tabaco/efectos adversos , Estudios de Evaluación como Asunto , Estudios Longitudinales , Modelos Animales , Depuración Mucociliar/fisiología , Contracción Muscular/fisiología , Estrés Oxidativo/fisiologíaRESUMEN
Oxidative stress is implicated in the neurobiology of depression. Here we investigated oxidative alterations in brain areas of animals submitted to the model of depression induced by corticosterone (CORT) and the effects of the antioxidant compound alpha-lipoic acid (ALA) alone or associated with the antidepressant desvenlafaxine (DVS) in these alterations. Female mice received vehicle or CORT (20 mg/kg) during 14 days. From the 15th to 21st days different animals received further administrations of: vehicle, DVS (10 or 20 mg/kg), ALA (100 or 200 mg/kg), or the combinations of DVS10+ALA100, DVS20+ALA100, DVS10+ALA200, or DVS20+ALA200. Twenty-four hours after the last drug administration prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were dissected for the determination of the activity of superoxide dismutase (SOD), reduced glutathione (GSH) and lipid peroxidation (LP) levels. CORT significantly increased SOD activity in the PFC and HC, decreased GSH levels in the HC and increased LP in all brain areas studied when compared to saline-treated animals. Decrements of SOD activity were observed in all groups and brain areas studied when compared to controls and CORT. The hippocampal decrease in GSH was reversed by ALA100, DVS10+ALA100, DVS20+ALA100 and DVS20+ALA200. The same DVS+ALA combination groups presented increased levels of GSH in the PFC and ST. The greater GSH levels were observed in the PFC, HC and ST of DVS20+ALA200 mice. LP was reversed in the groups ALA200 (PFC), DVS10+ALA100, DVS20+ALA100 (PFC, HC and ST), and DVS20+ALA200 (PFC, HC). Our findings contribute to the previous preclinical evidences implicating ALA as a promising agent for augmentation therapy in depression.
Asunto(s)
Antidepresivos/farmacología , Antioxidantes/farmacología , Trastorno Depresivo/tratamiento farmacológico , Succinato de Desvenlafaxina/farmacología , Estrés Oxidativo/efectos de los fármacos , Ácido Tióctico/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Corticosterona , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Glutatión/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/fisiología , Ratones , Estrés Oxidativo/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Distribución Aleatoria , Superóxido Dismutasa/metabolismoRESUMEN
The systemic administration of lipopolysaccharide (LPS) induces time-dependent behavioral alterations, which are related to sickness behavior and depression. The time-course effects of LPS on prepulse inhibition (PPI) remain unknown. Furthermore, the time-dependent effects of LPS on central nitrite content had not been investigated. Therefore, we studied alterations induced by single LPS (0.5mg/kg, i.p.) administration to mice on parameters, such as PPI, depressive- and anxiety-like behaviors, working memory, locomotor activity and motor coordination, 1.5 and 24h post-LPS administration. IL-1ß and TNFα in the blood and brain as well as brain nitrite levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). An overall hypolocomotion was observed 1.5h post-LPS, along with depressive-like behaviors and deficits in working memory. Increments in IL-1ß content in plasma and PFC, TNFα in plasma and decreases in nitrite levels in the ST and PFC were also verified. Twenty-four hours post-LPS treatment, depressive-like behaviors and working memory deficits persisted, while PPI levels significantly reduced along with increases in IL-1ß content in the PFC and a decrease in nitrite levels in the HC, ST and PFC. Our data demonstrate that a delayed increase (i.e., 24h post-LPS) in PPI levels ensue, which may be useful behavioral parameter for LPS-induced depression. A decrease in nitrergic neurotransmission was associated with these behavioral findings.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Inhibición Psicológica , Lipopolisacáridos/farmacología , Nitritos/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Citocinas/sangre , Citocinas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Óxido Nítrico/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Reflejo de Sobresalto/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Natación , Factores de TiempoRESUMEN
Tardive dyskinesia (TD) is an iatrogenic syndrome being a significant adverse outcome of typical and atypical antipsychotic therapy. Recently we demonstrated that vitamins B (B1, B6, B12 alone or in combination) were able to prevent haloperidol-induced orofacial dyskinesia (OD) possibly by their antioxidant activity in the striatum, using a well-established model of TD. Here, based on the fact that alterations in cholinergic neurotransmission are related to TD pathophysiology and that vitamins B seems to influence brain cholinergic neurotransmission, we decided to investigate the effects of vitamins B1, B6, B12 and their association, vitamin B cocktail in haloperidol-induced cholinergic alterations, evaluated by alterations in acetylcholinesterase (AChE) activity, in striatum, prefrontal cortex and hippocampus, as a way to determine the participation of cholinergic neurotransmission, in these vitamins antidyskinetic mechanism. Haloperidol 1 mg/kg i.p. daily administration during 21 days to Wistar rats caused OD while decreased AChE activity in all brain areas studied. Vitamins B administration (B1:B6:B12 at 60:60:0.6 mg/kg, s.c) alone and vitamin B cocktail co-administered with haloperidol prevented OD development and increased AChE activity in all brain areas studied, with the maximum activity increment observed in the hippocampus of the animals co-treated with vitamin B12 and vitamin B cocktail. The antidyskinetic drug, clozapine did not induce OD and increased AChE activity similarly to the groups coadministered with vitamin B and HAL. The present data suggest that vitamins B can prevent haloperidol-induced alterations in AChE activity what can be related to the mechanism underlying their antidyskinetic effect.
Asunto(s)
Acetilcolinesterasa/metabolismo , Antipsicóticos/toxicidad , Encéfalo/enzimología , Haloperidol/toxicidad , Trastornos del Movimiento/prevención & control , Complejo Vitamínico B/uso terapéutico , Animales , Masculino , Trastornos del Movimiento/enzimología , Ratas , Ratas WistarRESUMEN
This work examined the gastroprotection of (-)-α-bisabolol, an unsaturated optically active sesquiterpene alcohol obtained by the direct distillation essential oil from plants. (-)-α-Bisabolol has been described as a compound capable of reducing the gastric ulcer area in response to absolute ethanol. We evaluated the gastroprotection of (-)-α-bisabolol in ethanol-induced gastric lesions model through histopathological assessment, measurement of the membrane lipids peroxidation (MDA), myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, catalase (CAT) activity and the nitrite amount. Our results showed that (-)-α-bisabolol was able to reduce injuries associated with the administration of ethanol and the formation of thiobarbituric acid reactive substances (MDA) was also able to increase SOD activity and reduce the influx of cells inflammatory (neutrophils) in the gastric mucosa. The effect of (-)-α-bisabolol seems to be unrelated to the nitric oxide. (-)-α-Bisabolol caused a reduction of catalase activity. These findings show that (-)-α-bisabolol is able to decrease oxidative stress and inflammatory event associated with the lesions induced by ethanol.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Neutrófilos/patología , Sustancias Protectoras/farmacología , Sesquiterpenos/farmacología , Úlcera Gástrica/prevención & control , Superóxido Dismutasa/metabolismo , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Animales , Catalasa/metabolismo , Etanol/farmacología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/enzimología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos , Sesquiterpenos Monocíclicos , Neutrófilos/metabolismo , Nitritos/metabolismo , Peroxidasa/metabolismo , Sustancias Protectoras/uso terapéutico , Sesquiterpenos/uso terapéutico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patologíaRESUMEN
Tardive dyskinesia (TD) is a serious motor disorder related to antipsychotic therapy, whose pathophysiology is associated to oxidative stress. Treatments that maintain antipsychotic efficacy while reducing TD risk are awaited. Haloperidol (HAL), a typical antipsychotic, is used as a putative murine model of TD. Here, we evaluated the protective role of vitamins B1, B6, and B12 alone or in combination (vitamin B cocktail) in preventing the HAL-induced orofacial dyskinesia (OD), based on their antioxidant properties. HAL (1 mg/kg) administered intraperitoneally to Wistar rats for 21 days caused OD and increased catalepsy time. The daily administration of B vitamins (B1 : B6 : B12 at 60 : 60 : 0.6 mg/kg) alone or the vitamin B cocktail, along with HAL, prevented the development of OD. Catalepsy time reduced in all groups treated with B vitamins, but to a lesser extent than OD. The participation of oxidative stress was assessed by the determination of reduced glutathione (GSH) levels and lipid peroxide formation in the striatum. HAL significantly decreased GSH levels and enhanced lipid peroxidation, whereas B1, B12, and vitamin B cocktail prevented the decrease in GSH levels. All groups treated with B vitamins presented a decrease in lipid peroxide formation. The data suggest a promising role for B vitamins in the prevention of OD.
Asunto(s)
Antioxidantes/farmacología , Antipsicóticos/toxicidad , Conducta Animal , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Haloperidol/toxicidad , Trastornos del Movimiento/prevención & control , Complejo Vitamínico B/farmacología , Animales , Antioxidantes/uso terapéutico , Antipsicóticos/farmacología , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/fisiopatología , Glutatión/análisis , Glutatión/metabolismo , Haloperidol/farmacología , Peroxidación de Lípido/fisiología , Masculino , Malondialdehído/análisis , Malondialdehído/metabolismo , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/fisiopatología , Estrés Oxidativo , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/tratamiento farmacológico , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Complejo Vitamínico B/uso terapéuticoRESUMEN
OBJECTIVES: The antipsychotic, hypnotic, myorelaxant and antioxidant effects of the essential oil of Alpinia zerumbet (EOAZ) were studied. METHODS: EOAZ (50, 100 and 200 mg/kg i.p.) was administered once to mice for the determination of antipsychotic activity (evaluated by ketamine-induced hyperlocomotion), hypnotic activity (induced by sodium pentobarbital, 40 mg/kg i.p.), motor coordination (rotarod test), antioxidant effects (determination of lipid peroxidation and GSH levels), as well as alterations in nitric oxide levels (determination of nitrite content). KEY FINDINGS: EOAZ at doses of 100 and 200 mg/kg prevented ketamine hyperlocomotion, as did haloperidol (0.2 mg/kg i.p). EOAZ at a dose of 200 mg/kg decreased sleep latency, while all doses increased sleeping time. There was no effect on motor coordination. The in-vitro antioxidant capacity of the oil caused a decrease in lipid peroxidation and increase in GSH levels. EOAZ also prevented the decrease in nitrite content caused by oxidative stress. CONCLUSIONS: The results suggest antipsychotic and antioxidant effects for the EOAZ that may have promising efficacy for the treatment of schizophrenia.
Asunto(s)
Alpinia/química , Antioxidantes/farmacología , Antipsicóticos/farmacología , Hipnóticos y Sedantes/farmacología , Locomoción/efectos de los fármacos , Aceites Volátiles/farmacología , Esquizofrenia/fisiopatología , Animales , Antioxidantes/uso terapéutico , Antipsicóticos/uso terapéutico , Glutatión/metabolismo , Haloperidol/farmacología , Haloperidol/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Ketamina , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Nitritos/metabolismo , Aceites Volátiles/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Sueño/efectos de los fármacosRESUMEN
OBJECTIVES: Alpinia zerumbet, known in Brazil as colônia, is popularly used as a diuretic, antihypertensive, anti-ulcerogenic and sedative. Based on this, we have investigated the central effects of the essential oil isolated from A. zerumbet leaves. METHODS: Mice were treated once with 50 or 100 mg/kg of the essential oil, intraperitoneally, 30 min before being submitted to behavioural models of: locomotor activity (open-field), catalepsy, anxiety (elevated plus maze), depression (forced swimming test and tail suspension tests) as well as apomorphine-induced stereotypy. KEY FINDINGS: Results showed a dose-related decrease on locomotor activity and apomorphine-induced stereotypy. There was a decrease to the order of 55% of the grooming behaviour with both doses studied. The essential oil 100 mg/kg increased cataleptic activity (167%) and the immobility time in the forced swimming and tail suspension tests. Pretreatment with haloperidol (0.2 mg/kg, i.p.) alone also decreased locomotion, increased cataleptic activity and immobility time in the tail suspension test. No alterations in the elevated plus maze test were registered. CONCLUSIONS: The essential oil of A. zerumbet leaves had depressant and possible antipsychotic activity, since it could reverse the stereotypy induced by apomorphine, presenting effects comparable with those obtained with haloperidol treatment.