RESUMO
Iron overload contributes to the development of neurodegeneration and the exacerbation of normal apoptosis rates, largely due to its participation in the Fenton reaction and production of reactive oxygen species (ROS). Mitochondria constitute the major intracellular source of ROS and the main target of attack by free radicals. They are dynamic organelles that bind (fusion) and divide (fission) in response to environmental stimuli, developmental status, and energy needs of the cells. Sulforaphane (SFN) is a natural compound that displays antioxidant and anti-inflammatory activities. This study aims to investigate the effects of SFN on memory deficits and changes in markers of mitochondrial function, DNM1L and OPA1, and the synaptic marker, synaptophysin, induced by neonatal iron treatment. Male rats received vehicle or carbonyl iron (30mg/kg) from the 12th to the 14th postnatal day. In adulthood, they were treated with saline or SFN (0.5 or 5mg/kg) for 14days every other day. Memory deficits were assessed using the object recognition task. DNM1L, OPA1, and synaptophysin levels in the hippocampus were quantified by Western blotting. Results showed that SFN was able to reverse iron-induced decreases in mitochondrial fission protein, DNM1L, as well as synaptophysin levels in the hippocampus, leading to a recovery of recognition memory impairment induced by iron. These findings suggest that SFN may be further investigated as potential agent for the treatment of cognitive deficits associated with neurodegenerative disorders.
Assuntos
Anticarcinógenos/uso terapêutico , Compostos de Ferro/metabolismo , Isotiocianatos/uso terapêutico , Transtornos da Memória , Mitocôndrias/metabolismo , Sinapses/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Encéfalo/patologia , Catalase/genética , Catalase/metabolismo , Modelos Animais de Doenças , Dinaminas/genética , Dinaminas/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Ferro/metabolismo , Compostos de Ferro/toxicidade , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Mitocôndrias/patologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Gravidez , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , SulfóxidosRESUMO
The non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has been shown to produce cognitive deficits. However, the effects of ketamine on the consolidation phase of memory remain poorly characterized. Here we show that systemic administration of ketamine immediately after training dose-dependently impairs long-term retention of memory for a novel object recognition (NOR) task in rats. Control experiments showed that the impairing effects of ketamine could not be attributed to an influence on memory retrieval or sensorimotor effects. In addition, ketamine prevented the increase in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by NOR learning. Our results show for the first time that ketamine disrupts the consolidation phase of long-term recognition memory. In addition, the findings suggest that the amnestic effects of ketamine might be at least partially mediated by an influence on BDNF signaling in the hippocampus.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Aprendizagem , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Hipocampo/metabolismo , Masculino , Ratos , Fatores de TempoRESUMO
Increasing evidence indicates that iron deposition in the brain might play a role in cognitive dysfunction associated with neurodegenerative disorders and aging. Previous studies have not examined whether iron-induced memory deficits can be attenuated by acute treatments with memory-enhancing agents. Phosphodiesterase type 4 (PDE4) inhibitors such as rolipram (ROL) ameliorate memory impairments in several rodent models of amnesia and have been proposed as candidate cognitive-enhancing drugs. Here we show that a single posttraining systemic injection of ROL dose-dependently attenuates the impairment of memory for novel object recognition (NOR) in rats given neonatal iron loading, a model of iron-induced cognitive impairment. Posttraining administration of ROL also recovered NOR deficits associated with aging in rats. These findings provide the first evidence that stimulation of an intracellular second messenger signaling pathway can attenuate iron-induced memory impairment, and support the view that PDE4 inhibitors might ameliorate cognitive dysfunction associated with aging and neurodegenerative disorders.
Assuntos
Envelhecimento/efeitos dos fármacos , Ferro/efeitos adversos , Transtornos da Memória/etiologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Rolipram/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Transtornos da Memória/tratamento farmacológico , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD), are caused by different mechanisms but may share a common pathway to neuronal injury as a result of the overstimulation of glutamate receptors. It has been suggested that this pathway can be involved in generation of cognitive deficits associated with normal aging. Previous studies performed in our laboratory have demonstrated that aged rats presented recognition memory deficits. The aim of the present study was to evaluate the effect of memantine, a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, on age-induced recognition memory deficits. Additionally, parameters of oxidative damage in cerebral regions related to memory formation were evaluated. In order to do that, male Wistar rats (24 months old) received daily injections of saline solution or memantine (20 mg/kg i.p.) during 21 days. The animals were submitted to a novel object recognition task 1 week after the last injection. Memantine-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that memantine is able to reverse age-induced recognition memory deficits. We also demonstrated that memantine reduced the oxidative damage to proteins in cortex and hippocampus, two important brain regions involved in memory formation. Thus, the present findings suggest that, at least in part, age-induced cognitive deficits are related to oxidative damage promoted by NMDA receptor overactivation.
Assuntos
Envelhecimento/fisiologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Masculino , Transtornos da Memória/etiologia , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The gastrin-releasing peptide receptor (GRPR) has been implicated in central nervous system (CNS) diseases, including neurodevelopmental disorders associated with autism. In the present study we examined the effects of GRPR blockade during the neonatal period on behavioral measures relevant to animal models of neurodevelopmental disorders. Male Wistar rats were given an intraperitoneal (i.p.) injection of either saline (SAL) or the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095; 1 or 10mg/kg) twice daily for 10days from postnatal days (PN) 1 to 10. Animals treated with RC-3095 showed pronounced deficits in social interaction when tested at PN 30-35 and impaired 24-h retention of memory for both novel object recognition (NOR) and inhibitory avoidance (IA) tasks tested at PN 60-71. Neither short-term memory tested 1.5h posttraining nor open field behavior were affected by neonatal GRPR blockade. The implications of the findings for animal models of neurodevelopmental disorders are discussed.