RESUMO
The possible neuroprotector effects of pentoxifylline (P), a methylxanthine derivative and phosphodiesterase inhibitor, were studied on male Wistar rats subjected to a model of transient brain ischemia. One group was treated, 1 h before ischemia (ISC) and 1 h after, with pentoxifylline (P), 50 and 100 mg/kg, i.p. (ISC+P). The other groups were ischemic, ISC; sham operated, SO; P100; SO+P100; and normal controls, N. One week after ischemia, the animals were submitted to the open field, passive avoidance, and water maze tests for evaluating locomotor activity and cognitive deficits, as well as for scintillographic (SPECT) measurements. After these procedures, they were sacrificed and their brain dissected under ice, for histological studies as well as striatal dopamine (DA) and DOPAC measurements by HPLC. In the open field test, ischemia increased locomotor activity, as compared to N, SO, P100 and SO+P100. This parameter was not significantly reversed after P treatment (ISC+P50 or ISC+P100). Grooming behavior was also increased in the ISC group, as compared to all other ones, although only statistically different as compared to the P100 group. The P treatment (ISC+P50 and ISC+P100) brought these values close to normality. In the passive avoidance test, ischemia significantly impaired the short term memory, as compared to the N group, as well as scopolamine (SCP) used as a positive control. In the long term memory, similar effects were observed in the ISC and SCP groups that significantly impaired memory consolidation. P treatment completely reversed the effects observed after ischemia (ISC+P50 and ISC+P100) on the short as well as on the long term memory, and values were similar to those of the P100 group (which increased both parameters, as related to the N group). In the water maze, the ISC group was not different from the N, SO and SO+P100 groups. However, ISC+P50, ISC+P100 and P100 significantly improved the spatial memory, as related to all other groups. SPECT data showed that ischemia produced a lower but significant decrease in brain optical densities, and P brought values close to those seen in the N group. Furthermore, P treatment of the ischemic group (ISC+P50) increased the number of viable hippocampal CA3 neurons, as compared to the ISC group. While ischemia significantly decreased DA levels, the P treatment of ischemic animals brought those values close to normality. In conclusion, P counteracted neurological and neurochemical changes seen after brain ischemia, in rats. The TNF-alpha inhibition and anti-inflammatory actions of P could be responsible, at least in part, for the neuroprotection afforded by the drug.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Pentoxifilina/administração & dosagem , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/fisiopatologia , Isquemia Encefálica/fisiopatologia , Cognição/efeitos dos fármacos , Dopamina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Asseio Animal/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Escopolamina/farmacologiaRESUMO
Marine organisms have been shown to be potential sources of bioactive compounds with pharmaceutical applications. Previous chemical investigation of the nudibranch Tambja eliora led to the isolation of the alkaloid tambjamine D. Tambjamines have been isolated from marine sources and belong to the family of 4-methoxypyrrolic-derived natural products, which display promising immunosuppressive and cytotoxic properties. Their ability to intercalate DNA and their pro-oxidant activity may be related to some of the biological effects of the 4-methoxypyrrolic alkaloids. The aim of the present investigation was to determine the cytotoxic, pro-oxidant and genotoxic properties of tambjamine D in V79 Chinese hamster lung fibroblast cells. Tambjamine D displayed a potent cytotoxic effect in V79 cells (IC50 1.2 microg/mL) evaluated by the MTT assay. Based on the MTT result, V79 cells were treated with different concentrations of tambjamine D (0.6, 1.2, 2.4 and 4.8 microg/mL). After 24h, tambjamine D reduced the number of viable cells in a concentration-dependent way at all concentrations tested, assessed by the trypan blue dye exclusion test. The hemolytic assay showed that the cytotoxic activity of tambjamine D was not related to membrane disruption (EC50>100 microg/mL). Tambjamine D increased the number of apoptotic cells in a concentration-dependent manner at all concentrations tested according to acridine orange/ethidium bromide staining, showing that the alkaloid cytotoxic effect was related to the induction of apoptosis. MTT reduction was stimulated by tambjamine D, which may indicate the generation of reactive oxygen species. Accordingly, treatment of cells with tambjamine D increased nitrite/nitrate at all concentrations and TBARS production starting at the concentration corresponding to the IC50. Tambjamine D, also, induced DNA strand breaks and increased the micronucleus cell frequency as evaluated by comet and micronucleus tests, respectively, at all concentrations evaluated, showing a genotoxic risk induced by tambjamine D.
Assuntos
Produtos Biológicos/toxicidade , Fibroblastos/efeitos dos fármacos , Gastrópodes/química , Pulmão/efeitos dos fármacos , Mutagênicos/toxicidade , Alcaloides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Produtos Biológicos/química , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Dano ao DNA , Relação Dose-Resposta a Droga , Fibroblastos/patologia , Gastrópodes/metabolismo , Pulmão/patologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para MicronúcleosRESUMO
The anticonvulsant effects of hydroalcoholic extracts (HAEs) from the stem bark of Erythrina velutina and Erythrina mulungu on pentylenetetrazole (PTZ) and strychnine-induced seizure tests and the potentiation of pentobarbital-induced sleeping time in mice with the extracts were examined in this study. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. The extracts of Erythrina velutina (intraperitoneally or orally) and Erythrina mulungu (intraperitoneally) were administered in mice at single doses (200 or 400mg/kg). While Erythrina velutina and Erythrina mulungu did not exhibit any protector effect in PTZ-induced seizures, at any dose, an increase in the latency of convulsion and in the death time was observed with both doses and routes of Erythrina velutina and at higher dose of Erythrina mulungu, in strychnine-induced seizure. No alteration was observed with Erythrina velutina and Erythrina mulungu on sleeping latency at both doses as compared to control (362.8+/-59.5). However, the sleeping time was increased in both plants as compared to control (943.8+/-129.6). In conclusion, we showed that the hydroalcoholic extracts of Erythrina velutina and Erythrina mulungu have anticonvulsant effects only in the strychnine-induced seizure model, suggesting their possible action in glycine system and a potentiation of pentobarbital sleeping time, suggesting depressant action in the central nervous system.
Assuntos
Anticonvulsivantes/farmacologia , Erythrina , Extratos Vegetais/farmacologia , Convulsões/tratamento farmacológico , Administração Oral , Animais , Relação Dose-Resposta a Droga , Glicina/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Pentobarbital , Pentilenotetrazol , Fitoterapia , Plantas Medicinais , Convulsões/induzido quimicamente , Sono/efeitos dos fármacos , EstricninaRESUMO
The work shows the effects of caffeine after the intrastriatal injection of 6-OHDA in rats, considered as a model of Parkinson disease (PD). Two weeks after the 6-OHDA lesion, rats exhibit a characteristic rotation behavior as a response to the apomorphine challenge. Our results showed significant increases in the number of apomorphine-induced rotations in 6-OHDA-lesioned rats, as compared to sham-operated animals. A partial recovery was observed in 6-OHDA-lesioned rats, after caffeine (10 and 20 mg/kg, i.p., daily for 14 days) treatment. The stereotaxic injection of 6-OHDA produced loss of striatal neurons, as indicated by the decrease in monoamines levels, in the ipsilateral side (75-85%) when compared to the contralateral side. Significant decreases in noradrenaline levels were seen in the ipsilateral side of 6-OHDA group (62%), and this effect was not significantly reversed in caffeine-treated groups. While significant decreases in dopamine levels were seen in the ipsilateral side of 6-OHDA group (78%), in the caffeine-treated group (10 and 20 mg/kg, i.p.) the decreases were only 53 and 18%, indicating significant recoveries. In conclusion, our data demonstrated beneficial effects of caffeine in this model of PD, suggesting the potential use of A2A antagonists as a novel treatment for this neurodegenerative disease.
Assuntos
Cafeína/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxidopamina/metabolismo , Animais , Apomorfina/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encefalopatias/tratamento farmacológico , Cafeína/metabolismo , Modelos Animais de Doenças , Dopaminérgicos/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos WistarRESUMO
In this study we investigated the effects of Tenoxicam, a type 2 cyclooxygenase (COX-2) inhibitor, on brain damage induced by ischemia-reperfusion. Male Wistar rats (18-month old average) were anesthetized and submitted to ischemia occlusion of both common carotid arteries (BCAO) for 45 min. After 24 h of reperfusion, rats were decapitated and hippocampi removed for further assays. Animals were divided into sham-operated, ischemia, ischemia + Tenoxicam 2.5 mg/kg, and ischemia + Tenoxicam 10 mg/kg groups. Tenoxicam was administered intraperitoneally immediately after BCAO. Histological analyses show that ischemia produced significant striatal as well as hippocampal lesions which were reversed by the Tenoxicam treatment. Tenoxicam also significantly reduced, to control levels, the increased myeloperoxidase activity in hippocampus homogenates observed after ischemia. However, nitrite concentrations showed only a tendency to decrease in the ischemia + Tenoxicam groups, as compared to that of ischemia alone. On the other hand, hippocampal glutamate and aspartate levels were not altered by Tenoxicam. In conclusion, we showed that ischemia is certainly related to inflammation and to increased free radical production, and selective COX-2 inhibitors might be neuroprotective agents of potential benefit in the treatment of cerebral brain ischemia.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Piroxicam/análogos & derivados , Piroxicam/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Relação Dose-Resposta a Droga , Masculino , Fármacos Neuroprotetores/farmacologia , Nitritos/metabolismo , Piroxicam/farmacologia , Ratos , Ratos WistarRESUMO
Partial sleep deprivation is clinically associated with fatigue, depressive symptoms and reduced memory. Previously, it has been demonstrated that venlafaxine, an atypical antidepressant, increases the levels of noradrenaline and serotonin in rat hippocampus. The aim of this study was to evaluate the effects of venlafaxine on depression, anxiety, locomotor activity and memory in a model of REM sleep (REMs) deprivation in rats. We have also studied the influence of venlafaxine on monoamine levels in the striatum. Six groups of animals (N=20 each) were treated with saline or venlafaxine (1 or 10 mg/kg) during 10 days, submitted or not to REMs deprivation and studied with the forced swimming test of Porsolt (STP), plus-maze, passive avoidance and open-field tests right after sleep deprivation. Animals were also studied for passive avoidance 24 h later (rebound period). Brain samples for monoamine measurements were collected either immediately after REMs deprivation or after 24 h. Both REMs deprivation and venlafaxine showed an antidepressant effect. An anxiolytic effect was also observed after REMs deprivation. Previous treatment with venlafaxine blocked the antidepressant and anxiolytic effects of REMs deprivation. REMs deprivation alone and treatment with venlafaxine 10 mg/kg increased locomotor activity, and this effect was inhibited by venlafaxine in REMs deprived rats. Both venlafaxine treatment and REMs deprivation induced weight loss. Venlafaxine treatment, but not REMs deprivation, induced an increase in striatal dopamine (DA) levels. The combination of REMs deprivation and venlafaxine treatment was associated with an increase in serotonin turnover 24 h after rebound sleep. In this study, venlafaxine treatment hindered most behavioral effects of REMs deprivation and was associated with an interference on dopamine and serotonin systems in the striatum.
Assuntos
Peso Corporal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Cicloexanóis/farmacologia , Atividade Motora/efeitos dos fármacos , Privação do Sono/metabolismo , Animais , Peso Corporal/fisiologia , Corpo Estriado/metabolismo , Cicloexanóis/uso terapêutico , Feminino , Imobilização/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Privação do Sono/tratamento farmacológico , Cloridrato de VenlafaxinaRESUMO
This work studied the central behavioural effects of hydroalcoholic extracts from the stem bark of Erythrina velutina and Erythrina mulungu on the elevated plus maze, open field, and rota rod tests in mice. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. Single doses of the extracts were administered orally (200, 400 or 800 mg kg(-1)) or intraperitoneally (200 or 400 mg kg(-1)) to female mice. A reduction of the locomotor activity was observed in the open field test with both hydroalcoholic extracts after intraperitoneal treatment with all doses, but only with the highest dose after oral administration. In addition, oral and intraperitoneal administration of the extracts decreased the incidence of rearing and grooming. Decreases in the number of entries in the open (NEOA) and closed (NECA) arms of the elevated plus maze were observed after the administration of the highest dose (800 mg kg(-1), p.o.) of both hydroalcoholic extracts, and this effect may be due to the decrease in locomotor activity. These hydroalcoholic extracts failed to affect the motor coordination in the rota rod test. In conclusion, we showed that the hydroalcoholic extracts of E. velutina and E. mulungu have depressant effects on the central nervous system, which, at least partially, corroborates the popular use of these species as tranquilizers in Brazilian popular medicine.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Erythrina/química , Camundongos , Extratos Vegetais/farmacocinética , Plantas Medicinais , Administração Oral , Animais , Comportamento Animal , Brasil , Etanol , Comportamento Exploratório , Injeções Intraperitoneais , Masculino , Aprendizagem em Labirinto , Medicina Tradicional , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Casca de Planta , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , ÁguaRESUMO
Amburana cearensis a common tree found in Northeastern Brazil is widely used in folk medicine. The present work evaluated the cytotoxicity of kaempferol, isokaempferide, amburoside A and protocatechuic acid isolated from the ethanol extract of the trunk bark of A. cearensis. The compounds were tested for their cytotoxicity on the sea urchin egg development, hemolysis assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay using tumor cell lines. Isokaempferide and kaempferol, but not amburoside A and protocatechuic acid, inhibited the sea urchin egg development as well as tumor cell lines, but in this assay isokaempferide was more potent than kaempferol. Protocatechuic acid was the only compound able to induce hemolysis of mouse erythrocytes, suggesting that the cytotoxicity of kaempferol and isokaempeferide was not related to membrane damage.