RESUMO
Much evidence has suggested that early life adversity can have a lasting effect on behavior. The aim of this study was to explore the impact of prenatal exposure to stress on cognition in adult life and how it impacts chronic stress situations. In addition, we investigated the participation of glucocorticoids, neurotrophins and cytokines in prenatal stress effects. For this purpose, pregnant mice were placed in a cylindrical restraint tube for 2h daily during the last week of pregnancy. Control pregnant females were left undisturbed during their entire pregnancy period. Object-in-place task results showed that adult female mice exposed to prenatal stress exhibited an impairment in spatial memory. However, in the alternation test this memory deficit was only found in prenatally stressed mice submitted to chronic stress. This alteration occurred in parallel with a decrease in BDNF, an increase in glucocorticoid receptors and an alteration of Th1/Th2 in the hippocampus. Interestingly, these changes were observed in peripheral lymph nodes as well. However, none of the mentioned changes were observed in adult male mice. These results indicate that lymphoid cells could be good candidates as peripheral markers of susceptibility to behavioral alterations associated with prenatal exposure to stress.
Assuntos
Citocinas/metabolismo , Linfócitos/metabolismo , Transtornos da Memória/etiologia , Fatores de Crescimento Neural/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Animais , Encéfalo/metabolismo , Corticosterona/metabolismo , Citocinas/genética , Comportamento Exploratório , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/patologia , Camundongos , Fatores de Crescimento Neural/genética , Gravidez , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Reconhecimento Psicológico/fisiologiaRESUMO
It is widely known that ionizing radiation is a physical agent broadly used to kill tumor cells during human cancer therapy. Unfortunately, adjacent normal tissues can concurrently undergo undesirable cell injury. Previous data of our laboratory demonstrated that exposure of developing rats to ionizing radiations induced a variety of behavioral differences respect to controls, including changes in associative memory and in anxiety state. However, there is a lack of data concerning modifications in different related pharmacological intermediaries. Therefore, the aim of the present study was to investigate whether the behavioral differences observed in young animals irradiated at birth might be underlain by early changes in PKCß1 levels which, in turn, could lead to changes in hippocampal GABAergic neurotransmission. Male Wistar rats were irradiated with 5Gy of X rays between 24 and 48 h after birth. Different pharmacological markers related to the affected behavioral tasks were assessed in control and irradiated hippocampus at 15 and 30 days, namely GABAA receptor, GAD65-67, ROS and PKCß1. Results showed that all measured parameters were increased in the hippocampus of 30-days-old irradiated animals. In contrast, in the hippocampus of 15-days-old irradiated animals only the levels of PKCß1 were decreased. These data suggest that PKCß1 might constitute a primary target for neonatal radiation damage on the hippocampus. Therefore, it could be hypothesized that an initial decrease in the levels of this protein can trigger a subsequent compensatory increase that, in turn, could be responsible for the plethora of biochemical changes that might underlie the previously observed behavioral alterations.
Assuntos
Ansiedade/etiologia , Memória/efeitos da radiação , Animais , Feminino , Hipocampo/enzimologia , Hipocampo/metabolismo , Hipocampo/efeitos da radiação , Masculino , Proteína Quinase C beta/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de GABA-A/metabolismoRESUMO
Neonatal X-irradiation induces permanent abnormalities in cerebellar cortex cytoarchitecture and neurochemistry, as well as impairment in motor gait. The aim of the present work was to examine the potential protective properties of WR-2721 (Amifostine, Ethyol), a free radical scavenger, against the above mentioned alterations by using a previously described neuroprotection assessment protocol. Pre-irradiation treatment with amifostine was effective in partially preventing the cerebellar morphological damage and the motor gait impairment induced by ionizing radiation. No changes in cerebellar noradrenaline (NA) levels were detected in amifostine-treated irradiated animals. These results suggest that it is possible to counteract radiation-induced damage in the cerebella and motor gait of neonatal rats through oxygen free radical scavenger administration prior to irradiation. The presence of the agent before the injury occurs, favors the efficacy of amifostine neuroprotective activity. Clinical implications of this model are related to the daily exposure of many people to different sources of radiation (accidental, diagnostical or therapeutical).
Assuntos
Anormalidades Induzidas por Radiação/prevenção & controle , Amifostina/uso terapêutico , Animais Recém-Nascidos/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/efeitos da radiação , Fármacos Neuroprotetores , Protetores contra Radiação/uso terapêutico , Anormalidades Induzidas por Radiação/patologia , Animais , Animais Recém-Nascidos/anatomia & histologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/efeitos da radiação , Calbindinas , Feminino , Marcha/efeitos dos fármacos , Marcha/efeitos da radiação , Imuno-Histoquímica , Masculino , Norepinefrina/metabolismo , Fotomicrografia , Ratos , Ratos Wistar , Proteína G de Ligação ao Cálcio S100/metabolismo , Raios XRESUMO
Exposure of neonatal rats to a 5 Gy single dose of X-irradiation induces permanent abnormalities in cerebellar cortex cytoarchitecture and neurochemistry and motor function. This rodent model constitutes an useful tool to evaluate morphological, neurochemical and motor changes induced by ionizing radiation and the possible restorative effects of potential or clearly established neuroprotective drugs. After selection and administration of a neuroprotective agent to neonatally irradiated rats, quantitative evaluations of motor behavior (gait), cerebellar cortex cytoarchitecture and cerebellar monoamine levels are performed. Data are compared to those of both saline-injected, X-irradiated, and saline-injected, sham-irradiated controls. Evaluation of data from the different experimental groups is performed at postnatal days 30 and 90. After this postnatal interval, radiation-induced damage of cerebellar function in nonprotected rodents is considered to be permanent. The longitudinal evaluation of various parameters in the different experimental groups through a multidisciplinary approach, allows determination of the variables that are more sensitive to X-irradiation-induced damage and/or neuroprotective agent-induced restoration. Given the well-known correspondence in cerebellar developmental stages between rodents and humans, this model and related studies bring health-related implications, considering the accidental or therapeutic exposure of developing human beings to ionizing radiation.
Assuntos
Animais Recém-Nascidos/fisiologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/efeitos da radiação , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Protetores contra Radiação/farmacologia , Animais , Sistema Nervoso Central/metabolismo , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Marcha/efeitos dos fármacos , Imuno-Histoquímica , Indicadores e Reagentes , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Espectrometria de FluorescênciaRESUMO
Exposure of neonatal rats to a 5 Gy dose of X-irradiation induces permanent abnormalities in cerebellar cortex cytoarchitecture (disarrangement of Purkinje cells, reduction of thickness of granular cortex) and neurochemistry (late increase in noradrenaline levels), and motor function (ataxic gait). The neuroprotective effects of gangliosides have been demonstrated using a variety of CNS injuries, including mechanical, electrolytic, neurotoxic, ischemic, and surgical lesions. Here, we evaluated whether systemically administered GM1 ganglioside protects against the long-term CNS abnormalities induced by a single exposure to ionizing radiation in the early post-natal period. Thus, neonatal rats were exposed to 5 Gy X-irradiation, and subcutaneously injected with one dose (30 mg/kg weight) of GM1 on h after exposure followed by three daily doses. Both at post-natal days 30 and 90, gait and cerebellar cytoarchitecture in X-irradiated rats were significantly impaired when compared to age-matched controls. By contrast, both at post-natal days 30 and 90, gait in X-irradiated rats that were treated with GM1 was not significantly different from that in non-irradiated animals. Furthermore, at post-natal day 90, cerebellar cytoarchitecture was still well preserved in GM1-treated, X-irradiated animals. GM1 failed to modify the radiation-induced increase in cerebellar noradrenaline levels. Present data indicate that exogenous GM1, repeatedly administered after neonatal X-irradiation, produces a long-term radioprotection, demonstrated at both cytoarchitectural and motor levels.
Assuntos
Córtex Cerebelar/patologia , Gangliosídeo G(M1)/farmacologia , Neurônios Motores/efeitos da radiação , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Animais , Animais Recém-Nascidos , Córtex Cerebelar/fisiopatologia , Córtex Cerebelar/efeitos da radiação , Extremidades/fisiologia , Feminino , Marcha/fisiologia , Masculino , Neurônios Motores/química , Neurônios Motores/patologia , Norepinefrina/análise , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Ratos , Ratos WistarRESUMO
The activities of monoamine oxidases, MAO-A and MAO-B, were separately determined in the cerebellum (CE) from adult rats neonatally exposed to 5 Gy X-irradiation. They were found to be markedly reduced: 58% and 66% of values from nonirradiated, littermate controls. Since the specific activities of both isoenzymes (per mg tissue weight) were not significantly different from controls, the reduction of activity per CE is basically explained by the irradiation-induced cerebellar atrophy. The unmodified MAO-A specific activity makes it highly improbable that the increase in the cerebellar noradrenaline content, characteristic of neonatally X-irradiated rats, could be due to a decreased neuronal metabolism of noradrenaline by this enzyme.