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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >NMDA-induced neuroprotection in hippocampal neurons is mediated through the protein kinase A and CREB (cAMP-response element-binding protein) pathway.
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NMDA-induced neuroprotection in hippocampal neurons is mediated through the protein kinase A and CREB (cAMP-response element-binding protein) pathway.

机译：NMDA诱导的海马神经元神经保护作用是通过蛋白激酶A和CREB（cAMP反应元件结合蛋白）途径介导的。

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摘要

N-Methyl-d-aspartate (NMDA) receptors play a critical role in the brain stimulating synaptic plasticity and mediating neurodegeneration; a neuroprotective role has also been described, but its molecular mechanisms in hippocampus are under study. Here, we report that in primary cultures of rat hippocampal neurons exposure to low micromolar NMDA concentrations are neuroprotective against excitotoxic insults, while high micromolar NMDA concentrations provoke neuronal death. Molecular analysis reveals that a toxic concentration of NMDA induced a transient phosphorylation of cAMP-response element-binding protein (pCREB) in 2min that rapidly decreased below basal levels. In contrast, a nontoxic NMDA concentration gave up to longer (20min) rise of pCREB, suggesting that neuroprotection could be associated to a relatively prolonged presence of pCREB in the neurons. In support of this tenet, rolipram, an inhibitor of phosphodiesterase IV that increases the levels of cAMP and pCREB, protected against NMDA-induced neuronal death. Similar results were obtained with dibutyrate-cAMP (a cAMP analogue with membrane permeability) that also abrogated NMDA excitotoxicity. Conversely, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide (H89), an inhibitor of protein kinase A (PKA), that prevents the formation of pCREB induced by nontoxic NMDA concentrations, reverted the neuroprotection achieved by preincubation of low micromolar NMDA concentrations. These results substantiate the notion that induction of pCREB via PKA plays an important role in NMDA-mediated neuroprotection.
机译：N-甲基-d-天冬氨酸（NMDA）受体在大脑刺激突触可塑性和介导神经退行性变中起关键作用。还描述了神经保护作用，但是其在海马中的分子机制正在研究中。在这里，我们报告说，在大鼠海马神经元的原代培养中，暴露于低微摩尔NMDA浓度对兴奋性毒性损伤具有神经保护作用，而高微摩尔NMDA浓度则引起神经元死亡。分子分析显示，有毒浓度的NMDA会在2分钟内引起cAMP反应元件结合蛋白（pCREB）的短暂磷酸化，并迅速降至基础水平以下。相比之下，无毒的NMDA浓度则使pCREB的上升时间更长（20分钟），这表明神经保护作用可能与神经元中pCREB相对较长的存在有关。为了支持这一宗旨，咯利普兰是磷酸二酯酶IV的抑制剂，可增加cAMP和pCREB的水平，从而防止NMDA诱导的神经元死亡。用二丁酸-cAMP（具有膜渗透性的cAMP类似物）获得了相似的结果，该结果也消除了NMDA的兴奋性毒性。相反，蛋白激酶A（PKA）的抑制剂N- [2-（对溴肉桂酸氨基）乙基] -5-异喹啉磺酰胺（H89）阻止了无毒NMDA浓度诱导的pCREB的形成，从而逆转了通过低微摩尔NMDA浓度的预孵育。这些结果证实了通过PKA诱导pCREB在NMDA介导的神经保护中起重要作用的观点。

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