Moderate increases in intracellular calcium activate neuroprotective signals in hippocampal neurons
Moderate increases in intracellular calcium activate neuroprotective signals in hippocampal neurons
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DOI：
10.1016/j.neuroscience.2004.05.035
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发表时间：
2004-01-01
期刊：
影响因子：
3.3
通讯作者：
Fahlman, CS
中科院分区：
文献类型：
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作者：
Bickler, PE;Fahlman, CS
虽然神经元细胞内钙浓度（[Ca 2 +]（i））的大幅增加是致命的，但[Ca 2 +]（i）50-200 nM的中度增加可能诱导对缺血或其他应激的立即或长期耐受。在大鼠海马脑片培养的神经元中，我们确定了氧和葡萄糖剥夺（OGD）45分钟前后[Ca 2 +]（i）、细胞死亡和Ca 2+依赖性神经保护信号之间的关系。在OGD前30分钟，用1 nM-1 μ M的Ca 2+选择性离子载体（钙霉素或离子霉素-“Ca 2+预处理”）使CA 1神经元中的[Ca 2 +]（i）增加40-200 nM。尽管OGD后1小时预处理和对照神经元中的[Ca 2 +]i相似（约2 μ M），但在接下来的7天内，Ca 2+预处理大大减少了CA 1、CA 3和齿状回的细胞死亡。当pre-OGD [Ca 2 +]（i）降低到25 nM（10 nM离子载体，在无Ca 2+的培养基中）或增加到8 μ M（10 μ M离子载体）时，超过90%的神经元死亡。抗凋亡蛋白激酶B（Akt）和MAP激酶ERK（p42/44）的水平增加存在于OGD后的预处理切片中。减少Ca 2+内流，抑制钙调蛋白，并阻止Akt或MAP激酶p42/44上调阻止Ca 2+预处理，支持Ca 2+在神经保护过程中的特定作用。此外，在连续氧合培养的海马/皮质神经元中，用10 nM离子霉素预处理30分钟减少了由1 μ M离子霉素引起的[Ca 2 +]（i）增加4 μ M后的细胞死亡。因此，在潜在致死性损伤之前，[Ca 2 +]（i）适度增加的区域促进细胞存活，将随后的[Ca 2 +]（i）的大幅增加与启动细胞死亡过程解偶联。(C)2004年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Although large increases in neuronal intracellular calcium concentrations ([Ca2+](i)) are lethal, moderate increases in [Ca2+](i) of 50-200 nM may induce immediate or long-term tolerance of ischemia or other stresses. In neurons in rat hippocampal slice cultures, we determined the relationship between [Ca2+](i), cell death, and Ca2+-dependent neuroprotective signals before and after a 45 min period of oxygen and glucose deprivation (OGD). Thirty minutes before OGD, [Ca2+](i) was increased in CA1 neurons by 40-200 nM with I nM-1 muM of a Ca2+-selective ionophore (calcimycin or ionomycin-"Ca2+ preconditioning"). Ca2+ preconditioning greatly reduced cell death in CA1, CA3 and dentate during the following 7 days, even though [Ca2+]i was similar (approximately 2 muM) in preconditioned and control neurons 1 h after the OGD. When pre-OGD [Ca2+](i) was lowered to 25 nM (10 nM ionophore in Ca2+-free medium) or increased to 8 muM (10 muM ionophore), more than 90% of neurons died. Increased levels of the anti-apoptotic protein protein kinase B (Akt) and the MAP kinase ERK (p42/44) were present in preconditioned slices after OGD. Reducing Ca2+ influx, inhibiting calmodulin, and preventing Akt or MAP kinase p42/44 upregulation prevented Ca2+ preconditioning, supporting a specific role for Ca2+ in the neuroprotective process. Further, in continuously oxygenated cultured hippocampal/cortical neurons, preconditioning for 30 min with 10 nM ionomycin reduced cell death following a 4 muM increase in [Ca2+](i) elicited by 1 muM ionomycin. Thus, a zone of moderately increased [Ca2+](i) before a potentially lethal insult promotes cell survival, uncoupling subsequent large increases in [Ca2+](i) from initiating cell death processes. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.