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Objective Excessive release of excitatory amino acid and over increased intracellular Ca2+ could lead to hippocampus neurons over-excited, which contribute to excitotoxic cell death and finally developed severe cognitive impairment and motor deficits in epilepsy, stroke and other neurodegenerative diseases.However the mechanisms of neurons damage through proteins phosphorylation have not yet be clarified.In this study, we used kainic acid (KA)-induced neuronal excitotoxic model, investigate the effects of calcineurin (CaN) on regulation of the transcription factor CREB phosphorylation, which involves hippocampus structural and functional changes.Methods KA-indueed excitotoxic rats were given CaN inhibitors FK506 treatment and compare with saline.Morris water maze (MWM) was used to detect the functional changes of hippocampus in learning and memory, and toluidine blue staining to observe the structural changes in hippocampus.CREB phosphorylation was detected by Western blot.Results The learning and spatial memory of over-excited rats were significantly improved after CaN inhibition compared with the control group.There were considerable cell losses within hippocampal CA3 area of kainic acid over-excited rats.The neuronal cell losses were rescued significantly after treatment with FK506.Western blot analysis showed that rats received CaN inhibition have a significant increasing ofp-CREB compare with control animals.Conclusion Treatment with FK506 can reduce hippocampus neuronal damages of excitotoxic rats, thus improve learning and memory of rats.FK506 treatment also led to a significant increased level of CaN downstream targets p-CREB, which paralleled with the decrease of CaN activity.Suggesting that the activation of CaN may be involved in the regulation of cell survival, and play an important role in neuronal excitotoxic injury.