RESUMO
In this work, the effect of a single dose of diazepam was tested on different markers of oxidative damage in the striatum of rats in an acute model of immobilization (restraint) stress. In addition, the locomotor activity was measured at the end of the restraint period. Immobilization was induced to animals for 24 hr, and then, lipid peroxidation, superoxide dismutase activity and content, and mitochondrial function were all estimated in striatal tissue samples. Corticosterone levels were measured in serum. Diazepam was given to rats as a pre-treatment (1 mg/kg, i.p.) 20 min. before the initiation of stress. Our results indicate that acute stress produced enhanced striatal levels of lipid peroxidation (73% above the control), decreased superoxide dismutase activity (54% below the control), reduced levels of mitochondrial function (35% below the control) and increased corticosterone serum levels (86% above the control). Pre-treatment of stressed rats with diazepam decreased the striatal lipid peroxidation levels (68% below the stress group) and improved mitochondrial function (18% above the stress group), but only mild preservation of superoxide dismutase activity was detected (17% above the stress group). In regard to the motor assessment, only the stereotyped activity was increased in the stress group with respect to control (46% above the control), and this effect was prevented by diazepam administration (30% below the stress group). The preventive actions of diazepam in this acute model of stress suggest that drugs exhibiting anxiolytic and antioxidant properties might be useful for the design of therapies against early acute phases of physic stress.
Assuntos
Ansiolíticos/farmacologia , Antioxidantes/farmacologia , Diazepam/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Estresse Fisiológico , Animais , Western Blotting , Corticosterona/sangue , Imobilização , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
This work focuses on the effect of acute stress on different markers of oxidative stress and mitochondrial dysfunction in the rat striatum. In addition, the effect of a single dose of l-carnitine (l-CAR, 300 mg/kg, i.p.) was evaluated in these animals. Immobilization (restraint) stress was induced to rats for 24 hr. The levels of lipid peroxidation (LP) and mitochondrial function (MF), as well as the superoxide dismutase (SOD) activity and content and reduced glutathione (GSH) levels, were all measured in striatal samples of animals subjected to stress. Our results indicate that acute stress is able to increase the striatal LP and reduced the levels of MF, while significantly lowered the manganese superoxide dismutase (Mn-SOD) activity. No changes were observed in the total striatal content of SOD, nor in GSH levels, but serum corticosterone content was increased by stress. l-CAR exhibited partial protective effects on the immobilized group, reducing the striatal LP and recovering the striatal MF and Mn-SOD activity. Our results suggest that acute restraint stress brings an accurate model for early pro-oxidant responses that can be targeted by broad-spectrum antioxidants like l-CAR.
Assuntos
Carnitina/farmacologia , Corpo Estriado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/metabolismo , Doença Aguda , Animais , Corpo Estriado/efeitos dos fármacos , Corticosterona/sangue , Peroxidação de Lipídeos , Masculino , Mitocôndrias/fisiologia , Ratos , Ratos Wistar , Restrição Física , Superóxido Dismutase/metabolismoRESUMO
Amyloid beta (Abeta) peptide exerts different toxic effects at a cellular level, including over-activation of N-methyl-D-aspartate receptor (NMDAr) and excitotoxicity, synaptic dysfunction and neuronal death. Kynurenic acid (KYNA) is an endogenous antagonist of NMDAr and alpha7 nicotinic receptors. Systemic administrations of both the immediate metabolic precursor of KYNA, L-kynurenine (L-KYN), and a proved inhibitor of KYNA's brain transport, probenecid (PROB), have shown to produce neuroprotective effects in a considerable number of experimental toxic conditions; however, this strategy has not been tested in the toxic model Abeta peptide so far. In this study we evaluated the effects of systemic administration of PROB (50 mg/kg/day for 7 days), L-KYN (75 mg/kg/day for 7 days) and their combination, on behavioural (locomotor activity and spatial memory) and morphological alterations induced by an intrahippocampal infusion of Abeta 25-35 to rats. An additional group was administered with the potent NMDAr antagonist dizocilpine (MK-801, 0.8 mg/kg/day for 7 days) for comparative purposes. A significant improvement of spatial memory was evident in Abeta-lesioned rats since post-lesion day 21 with all treatments tested and this effect was correlated with a reduction of cell damage and a decrease in reactive gliosis in hippocampal CA1 area. Neither L-KYN, nor PROB, or their combination, produced major alterations in motor function when given alone to rats. These results suggest that modulation of NMDAr activity by mean of therapeutic strategies designed to enhance KYNA in the brain may help to counteract neurodegenerative events coursing with Abeta toxicity and excitotoxic patterns.