RESUMO
Acute organophosphate (OP) poisoning, particularly by suicide attempts, generates high mortality and morbidity. Few studies have systematically addressed the consequences of acute OP intoxication on cognition and memory of survivors. Preclinical evidence suggests that acute OP-induced effects are associated with inhibiting the brain acetylcholinesterase (AChE) enzyme. The OP triazophos has been used worldwide, although its effects on mnemonic processing are yet to be investigated. Based on the above, the present study investigated whether acute triazophos intoxication interferes with the expression and extinction of contextual fear memory in rats. Hippocampal and amygdalar AChE activity and plasma butyrylcholinesterase (BChE) were measured at the end of the experiment to confirm the cholinergic overstimulation. Independent cohorts of animals intoxicated with triazophos were evaluated in the novel object recognition (NOR) test, a less aversive associative memory task. At the dose of 15 mg/kg, triazophos administered immediately after contextual fear conditioning impaired the extinction but not the expression of freezing behavior. Triazophos poisoning induced no changes in the discrimination index in the NOR test. Triazophos inhibited the AChE activity in a time- and brain region-dependent manner. Our findings suggest that fear memory extinction deficits induced by acute triazophos intoxication are accompanied by hippocampal AChE inhibition. The deficient fear extinction associated with acute OP poisoning may represent a behavioral and biochemical phenotype helpful to study mechanisms of neurotoxicity and treatment approach of OP suicide survivors.
Assuntos
Inibidores da Colinesterase/toxicidade , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Organofosfatos/toxicidade , Organotiofosfatos/toxicidade , Triazóis/toxicidade , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Condicionamento Clássico/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Ratos , Ratos WistarRESUMO
Galanin is a neuropeptide distributed in human and rat brain regions that are involved with emotional regulation, such as the dorsal raphe nucleus (DRN). Galanin effects in the DRN are mediated by GAL1 and GAL2 receptors. Intracerebral infusion of a GAL2 (AR-M1896) or a GAL1 (M617) agonist induced either antidepressant or depressive-like effect, respectively, in rats exposed to the forced swimming test (FST). However, it is not clear if GAL1 and/or GAL2 receptors present in the DRN would be involved in such effects. Therefore, we investigated the effects induced by intra-DRN infusion of galanin (0.3â¯nmol), AR-M1896 (1â¯nmol, GAL2 agonist), or M617 (GAL1 agonist) in rats exposed to the FST. Galanin and AR-M1896 intra-DRN administration induced antidepressant-like effect in the FST. However, M617 did not induce any change in the FST. Neither M617 nor AR-M1896 changed the locomotor activity of rats in the open field test. Intra-DRN pre-treatment with M871 (1â¯nmol), a selective GAL2 antagonist, counteracted the antidepressant-like effect induced by galanin. These results suggest that galanin signaling through GAL2 receptors in the DRN produces triggers antidepressant-like effect.
Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Núcleo Dorsal da Rafe/fisiologia , Galanina/administração & dosagem , Precursores de Proteínas/administração & dosagem , Receptor Tipo 2 de Galanina/fisiologia , Animais , Depressão/psicologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Fragmentos de Peptídeos/administração & dosagem , Peptídeos/administração & dosagem , Ratos , Ratos Wistar , Receptor Tipo 2 de Galanina/agonistas , Receptor Tipo 2 de Galanina/antagonistas & inibidores , Natação/fisiologia , Natação/psicologia , Resultado do TratamentoRESUMO
Na+, K+-ATPase is an important regulator of brain excitability. Accordingly, compelling evidence indicates that impairment of Na+, K+-ATPase activity contributes to seizure activity in epileptic mice and human with epilepsy. In addition, this enzyme is crucial for plasma membrane transport of water, glucose and several chemical mediators, including glutamate, the major excitatory transmitter in the mammalian brain. Since glucose hypometabolism and increased glutamate levels occur in clinical and experimental epilepsy, we aimed the present study to investigate whether activation of Na+, K+-ATPase activity with specific antibody (DRRSAb) would improve glucose uptake and glutamate release in pilocarpine-treated mice. We found decreased uptake of the glucose fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-il)amino]-2-desoxi-d-glucose (2-NBDG) in cerebral slices from pilocarpine-treated animals. Interestingly, decreased 2-NBDG uptake was not detected in DRRSAb-treated slices, suggesting a protective effect of the Na+, K+-ATPase activator. Moreover, DRRSAb prevented the increase in glutamate levels in the incubation media of slices from pilocarpine-treated mice. In addition, in vivo intrahippocampal injection of DRRSAb restored crossing activity of pilocarpine-treated mice in the open-field test. Overall, the present data further support the hypothesis that activation of the Na+, K+-ATPase is a promising therapeutic strategy for epilepsy.
Assuntos
Anticorpos/farmacologia , Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , ATPase Trocadora de Sódio-Potássio/imunologia , Animais , Caspase 3/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Epilepsia/metabolismo , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Oxirredução/efeitos dos fármacos , Pilocarpina , ATPase Trocadora de Sódio-Potássio/metabolismo , Técnicas de Cultura de TecidosRESUMO
OBJECTIVES: Epilepsy is a common brain disease and a major worldwide public health problem. The seizures in a significant number of patients suffering from epilepsy remain inadequately controlled by currently available pharmacological treatments. Accordingly, there is a need for the discovery of new anticonvulsant approaches with improved efficacy and a better safety profile. In this context, natural products can be a valuable source of substances with potential anticonvulsant activity. In the present study, we tested the anticonvulsant potential of Caryocar coriaceum Wittm., a plant native from the Brazilian Cerrado biome (tropical savanna ecoregion). METHODS: Adult male C57BL/6 mice were treated with increasing doses of the fixed oil obtained from the pulp of Caryocar coriaceum Wittm. Seizure activity was induced by PTZ (60 mg/kg, i.p.), and evaluated by behavioral and electrographic methods. Potential adverse effects were investigated in the open-field, rotarod, forced swim, or object recognition tests. The antioxidant potential of the oil was evaluated by the DPPH scavenging assay. RESULTS: Administration of the oil at the dose of 100 mg/kg increased the latency for the first myoclonic jerk and the first generalized tonic-clonic seizures. The duration of generalized convulsions induced by PTZ was not altered. No significant behavioral adverse effects were detected in the open-field, rotarod, forced swim, or object recognition tests. Interestingly, a significant antioxidant activity of Caryocar coriaceum Wittm. fixed pulp oil was detected in the DPPH scavenging assay. DISCUSSION: Natural products can be a valuable source of substances with potential anticonvulsant activity and improved safety profile. Further studies are needed to evaluate the mechanisms underlying the anticonvulsant effects of Caryocar coriaceum Wittm. fixed pulp oil as well as the potential of the oil as a source of new anticonvulsant compounds.
Assuntos
Anticonvulsivantes/farmacologia , Ericales , Óleos de Plantas/farmacologia , Convulsões , Animais , Convulsivantes/toxicidade , Eletroencefalografia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamenteRESUMO
Spermidine (SPD) is an endogenous aliphatic amine that modulates GluN2B-containing NMDA receptors and improves memory. Recent evidence suggests that systemic SPD improves the persistence of the long term memory of fear. However, the role of hippocampal polyamines and its binding sites in the persistence of fear memory is to be determined, as well as its putative underlying mechanisms. This study investigated whether the intrahippocampal (i.h.) infusion of spermidine or arcaine, modulators of polyamine binding site at GluN2B-containing NMDA receptors, alters the persistence of the memory of contextual fear conditioning task in rats. We also investigated whether protein synthesis and cAMP dependent protein kinase (PKA) play a role in SPD-induced improvement of the fear memory persistence. While 12h post-training infusion of spermidine facilitated, arcaine and the inhibitor of protein synthesis (anisomycin) impaired the memory of fear assessed 7days after training. The infusion of arcaine, anisomycin or a selective PKA inhibitor (H-89), at doses that have no effect on memory per se, prevented the SPD-induced improvement of memory persistence. H-89 prevented the stimulatory effect of SPD on phospho-PKA/total-PKA ratio. These results suggests that the improvement of fear memory persistence induced by spermidine involves GluN2B-containing NMDA receptors, PKA pathway and protein synthesis in rats.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Medo/fisiologia , Hipocampo/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Nootrópicos/farmacologia , Poliaminas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Espermidina/farmacologia , Animais , Anisomicina/administração & dosagem , Anisomicina/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Biguanidas/administração & dosagem , Biguanidas/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacologia , Masculino , Nootrópicos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores da Síntese de Proteínas/administração & dosagem , Ratos , Ratos Wistar , Espermidina/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologiaRESUMO
Increasing evidence suggests that plant-derived extracts and their isolated components are useful for treatment of seizures and, hence, constitute a valuable source of new antiepileptic drugs with improved efficacy and better adverse effect profile. ß-Caryophyllene is a natural bicyclic sesquiterpene that occurs in a wide range of plant species and displays a number of biological actions, including neuroprotective activity. In the present study, we tested the hypothesis that ß-caryophyllene displays anticonvulsant effects. In addition, we investigated the effect of ß-caryophyllene on behavioral parameters and on seizure-induced oxidative stress. Adult C57BL/6 mice received increasing doses of ß-caryophyllene (0, 10, 30, or 100mg/kg). After 60 min, we measured the latencies to myoclonic and generalized seizures induced by pentylenetetrazole (PTZ, 60 mg/kg). We found that ß-caryophyllene increased the latency to myoclonic jerks induced by PTZ. This result was confirmed by electroencephalographic analysis. In a separate set of experiments, we found that mice treated with an anticonvulsant dose of ß-caryophyllene (100mg/kg) displayed an improved recognition index in the object recognition test. This effect was not accompanied by behavioral changes in the open-field, rotarod, or forced swim tests. Administration of an anticonvulsant dose of ß-caryophyllene (100mg/kg) did not prevent PTZ-induced oxidative stress (i.e., increase in the levels of thiobarbituric acid-reactive substances or the decrease in nonprotein thiols content). Altogether, the present data suggest that ß-caryophyllene displays anticonvulsant activity against seizures induced by PTZ in mice. Since no adverse effects were observed in the same dose range of the anticonvulsant effect, ß-caryophyllene should be further evaluated in future development of new anticonvulsant drugs.
Assuntos
Anticonvulsivantes/uso terapêutico , Convulsivantes , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Epilepsias Mioclônicas/induzido quimicamente , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos Policíclicos , Equilíbrio Postural/efeitos dos fármacos , Reconhecimento Psicológico , Convulsões/psicologia , Natação/psicologiaRESUMO
OBJECTIVE: Verify the role of the kinin B1 receptors (B1R) and the effect of ACE inhibitors (ACEi) on acute gout induced by monosodium urate (MSU) crystals in rodents. METHODS: Painful (overt pain and allodynia) and inflammatory parameters (joint oedema, leukocyte trafficking, interleukin-1ß levels) of acute gout attacks were assessed several hours after an intra-articular injection of MSU (1.25 or 0.5 mg/articulation) into the ankle of rats or mice, respectively. The role of B1R was investigated using pharmacological antagonism or gene deletion. Additionally, B1R immunoreactivity in ankle tissue and sensory neurons, kininase I activity and des-Arg(9)-bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on a low dose of MSU (0.0125 mg/articulation)-induced inflammation. RESULTS: Kinin B1R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased B1R expression in articular tissues, the content of the B1 agonist des-Arg(9)-bradykinin and the activity of the B1 agonist-forming enzyme kininase I. A low dose of MSU crystals, which did not induce inflammation in control animals, caused signs of acute gout attacks in ACEi-treated animals that were B1R-dependent. CONCLUSIONS: Kinin B1R contributes to acute gouty attacks, including the ones facilitated by ACEi. Therefore, B1R is a potential therapeutic target for the treatment and prophylaxis of gout, especially in patients taking ACEi.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Gota/metabolismo , Receptor B1 da Bradicinina/fisiologia , Doença Aguda , Animais , Antagonistas de Receptor B1 da Bradicinina/uso terapêutico , Dioxóis/uso terapêutico , Edema/induzido quimicamente , Edema/metabolismo , Gota/induzido quimicamente , Gota/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dor/induzido quimicamente , Dor/metabolismo , Ratos Wistar , Sulfonamidas/uso terapêutico , Ácido ÚricoRESUMO
Together with pharmacoresistant seizures, the quality of life of temporal lobe epilepsy (TLE) patients is negatively impacted by behavioral comorbidities including but not limited to depression, anxiety and cognitive deficits. The pilocarpine model of TLE has been widely used to study characteristics of human TLE, including behavioral comorbidities. Since the outcomes of pilocarpine-induced TLE might vary depending on several experimental factors, we sought to investigate potential gender-related differences regarding selected behavioral alterations in C57BL6 mice. We found that epileptic mice, independent of gender, displayed increased anxiety-like behavior in the open-field test. In the object recognition test, epileptic mice, regardless of gender, showed a decreased recognition index at 24 (but not at 4) hours after training. On the other hand, no significant differences were found regarding mice learning and memory performance in the Barnes maze paradigm. Motor coordination and balance as assessed by the beam walk and rotarod tests were not impaired in epileptic mice of both genders. However, female mice, independent of epilepsy, performed the beam walk and rotarod tasks better than their male counterparts. We also found that only male epileptic mice displayed disturbed behavior in the forced swim test, but the mice of both genders displayed anhedonia-like behavior in the taste preference test. Lastly, we found that the extent of hilar cell loss is similar in both genders. In summary, both genders can be successfully employed to study behavioral comorbidities of TLE; however, taking the potential gender differences into account may help choose the more appropriated gender for a given task, which may be of value for the minimization of the number of animals used during the experiments.
Assuntos
Transtornos Cognitivos/etiologia , Transtornos Mentais/etiologia , Caracteres Sexuais , Estado Epiléptico/complicações , Fatores Etários , Análise de Variância , Animais , Anticonvulsivantes/uso terapêutico , Diazepam/uso terapêutico , Modelos Animais de Doenças , Feminino , Preferências Alimentares/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Agonistas Muscarínicos/toxicidade , Pilocarpina/toxicidade , Equilíbrio Postural/efeitos dos fármacos , Transtornos Psicomotores/etiologia , Reconhecimento Psicológico , Estado Epiléptico/induzido quimicamente , Natação/psicologiaRESUMO
Male mice received lycopene for 10 days before a single oral administration of zearalenone (ZEA). After 48 h testes and blood were collected. Mice treated with lycopene/ZEA exhibited amelioration of the hematological changes. Lycopene prevented the reduction in the number and motility of spermatozoa and testosterone levels, indicating a protective effect in the testicular damage induced by ZEA. Lycopene was also effective in protecting against the decrease in glutathione-S-transferase, glutathione peroxidase, glutathione reductase and δ-aminolevulinic acid dehydratase activities caused by ZEA in the testes. Exposure of animals to ZEA induced modification of antioxidant and inflammatory status with increase of reduced glutathione (GSH) levels and increase of the oxidized glutathione, interleukins 1ß, 2, 6, 10, tumor necrosis factor-α and bilirubin levels. Lycopene prevented ZEA-induced changes in GSH levels and inhibited the processes of inflammation, reducing the damage induced by ZEA. Altogether, our results indicate that lycopene was able to prevent ZEA-induced damage in the mice.
Assuntos
Carotenoides/farmacologia , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Testículo/efeitos dos fármacos , Zearalenona/toxicidade , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Bilirrubina/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Inflamação/metabolismo , Interleucinas/metabolismo , Licopeno , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Sintase do Porfobilinogênio/metabolismo , Testículo/patologia , Testosterona/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Zearalenona/administração & dosagemRESUMO
Temporal lobe epilepsy (TLE) is the most common type of epilepsy with about one third of TLE patients being refractory to antiepileptic drugs. Knowledge about the mechanisms underlying seizure activity is fundamental to the discovery of new drug targets. Brain Na(+),K(+)-ATPase activity contributes to the maintenance of the electrochemical gradients underlying neuronal resting and action potentials as well as the uptake and release of neurotransmitters. In the present study we tested the hypothesis that decreased Na(+),K(+)-ATPase activity is associated with changes in the alpha subunit phosphorylation and/or redox state. Activity of Na(+),K(+)-ATPase decreased in the hippocampus of C57BL/6 mice 60 days after pilocarpine-induced status epilepticus (SE). In addition, the Michaelis-Menten constant for ATP of α2/3 isoforms increased at the same time point. Nitration of the α subunit may underlie decreased Na(+),K(+)-ATPase activity, however no changes in expression or phosphorylation state at Ser(943) were found. Further studies are necessary define the potential of nitrated Na(+),K(+)-ATPase as a new therapeutic target for seizure disorders.