Calcium preconditioning triggers neuroprotection in retinal ganglion cells.
Calcium preconditioning triggers neuroprotection in retinal ganglion cells.
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DOI：
10.1016/j.neuroscience.2010.10.071
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发表时间：
2011-01-13
期刊：
影响因子：
3.3
通讯作者：
Linn, C. L.
中科院分区：
文献类型：
--
作者：
Brandt, S. K.;Weatherly, M. E.;Ware, L.;Linn, D. M.;Linn, C. L.
在哺乳动物视网膜中，已显示兴奋性毒性涉及凋亡性视网膜神经节细胞（RGC）死亡，并且与某些视网膜疾病状态相关，包括青光眼、糖尿病性视网膜病变和视网膜缺血。本实验室以前的研究表明，乙酰胆碱（ACh）和尼古丁通过烟碱乙酰胆碱受体（nAChRs）在分离的成年猪RGC中保护谷氨酸诱导的兴奋性毒性。这些RGC中nAChR的激活触发细胞存活信号传导途径并抑制凋亡酶。然而，nAChR的结合和神经保护通路的激活之间的联系是未知的。在这项研究中，我们检验了这样的假设：在分离的猪RGC中，乙酰胆碱诱导的神经保护作用需要钙通过nAChR通道渗透，以对抗谷氨酸诱导的兴奋性毒性。使用两步淘选技术从其他视网膜组织中分离RGC，并在不同条件下培养3天。在一些研究中，使用荧光钙指示剂fluo-4进行钙成像实验，并证明钙渗透位于猪RGC上的nAChR通道。在其他研究中，改变细胞外钙浓度以确定对尼古丁诱导的神经保护作用的影响。结果支持这一假设，钙是尼古丁诱导的神经保护作用所需的分离的猪RGC。最后，研究预处理对谷氨酸兴奋毒性的影响及神经保护作用。在这些研究中，在对细胞施加大的谷氨酸损伤之前，使用各种机制将预处理剂量的钙引入细胞。这些研究的结果支持了这样的假设，即在兴奋性毒性损伤之前，用相对低水平的钙对细胞进行预处理会导致神经保护。在未来，这些结果可以提供重要的信息有关的治疗药物开发，以打击各种疾病涉及谷氨酸诱导的兴奋性毒性。
In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes. However, the link between binding of nAChRs and activation of neuroprotective pathways is unknown. In this study, we examine the hypothesis that calcium permeation through nAChR channels is required for ACh-induced neuroprotection against glutamate-induced excitotoxicity in isolated pig RGCs. RGCs were isolated from other retinal tissue using a two step panning technique and cultured for 3 days under different conditions. In some studies, calcium imaging experiments were performed using the fluorescent calcium indicator, fluo-4, and demonstrated that calcium permeates the nAChR channels located on pig RGCs. In other studies, the extracellular calcium concentration was altered to determine the effect on nicotine-induced neuroprotection. Results support the hypothesis that calcium is required for nicotine-induced neuroprotection in isolated pig RGCs. Lastly, studies were performed to analyze the effects of preconditioning on glutamate-induced excitotoxicity and neuroprotection. In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before an excitotoxic insult leads to neuroprotection. In the future, these results could provide important information concerning therapeutic agents developed to combat various diseases involved with glutamate-induced excitotoxicity.
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