Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia
Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia
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DOI：
10.1046/j.1471-4159.2001.00258.x
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发表时间：
2001-04-01
影响因子：
4.7
通讯作者：
Rosenbaum, DM
中科院分区：
文献类型：
--
作者：
Singh, M;Savitz, SI;Rosenbaum, DM
新的证据支持半胱天冬酶在缺血再灌注损伤后神经元死亡中的重要作用。本研究评估了细胞特异性半胱天冬酶是否参与神经元变性以及半胱天冬酶抑制是否在短暂性视网膜缺血后提供神经保护。我们利用短暂性整体视网膜缺血模型。确定缺血性损伤后视网膜神经元中 caspase 1、2 和 3 表达活性形式的空间和时间模式。使用细胞特异性标记物进行双重标记可识别哪些细胞表达不同的半胱天冬酶。在单独的实验中，动物在诱导缺血之前接受各种半胱天冬酶抑制剂。 60 分钟的缺血导致 7 天时视网膜内层延迟的、选择性的神经元死亡。在任何时间点均未检测到 caspase 1 的表达。 Caspase 2 的最大表达在 24 小时时发现，主要在视网膜的内核和神经节细胞层中，并且定位于神经节和无长突神经元。 Caspase 3 也在内核层和外核层中于 24 小时达到峰值，主要在感光细胞中表达，在无长突神经元中表达较少。泛 caspase 抑制剂 Boc-aspartyl fmk 或 caspase 2 反义寡核苷酸抑制剂在 7 天时导致显着的组织病理学和功能改善（视网膜电图）。 Caspase 1 选择性抑制剂 Y-vad fmk 未发现任何保护作用。这些观察结果表明，缺血再灌注损伤根据视网膜中的神经元表型激活不同的半胱天冬酶，并且半胱天冬酶抑制导致组织学保存和功能改善。 Caspases 2 和 3 可能在缺血再灌注后的无长突神经元中并行作用。视网膜中的这些结果可能揭示全脑缺血中不同的 caspase 特异性。
Emerging evidence supports an important role for caspases in neuronal death following ischemia-reperfusion injury. This study assessed whether cell specific caspases participate in neuronal degeneration and whether caspase inhibition provides neuroprotection following transient retinal ischemia. We utilized a model of transient global retinal ischemia. The spatial and temporal pattern of the active forms of caspase 1, 2 and 3 expression was determined in retinal neurons following ischemic injury. Double-labeling with cell-specific markers identified which cells were expressing different caspases. In separate experiments, animals received various caspase inhibitors before the induction of ischemia. Sixty minutes of ischemia resulted in a delayed, selective neuronal death of the inner retinal layers at 7 days. Expression of caspase 1 was not detected at any time point. Maximal expression of caspase 2 was found at 24 h primarily in the inner nuclear and ganglion cell layers of the retina and localized to ganglion and amacrine neurons. Caspase 3 also peaked at 24 h in both the inner nuclear and outer nuclear layers and was predominantly expressed in photoreceptor cells and to a lesser extent in amacrine neurons. The pan caspase inhibitor, Boc-aspartyl fmk, or an antisense oligonucleotide inhibitor of caspase 2 led to significant histopathologic and functional improvement (electroretinogram) at 7 days. No protection was found with the caspase 1 selective inhibitor, Y-vad fmk. These observations suggest that ischemia-reperfusion injury activates different caspases depending on the neuronal phenotype in the retina and caspase inhibition leads to both histologic preservation and functional improvement. Caspases 2 and 3 may act in parallel in amacrine neurons following ischemia-reperfusion. These results in the retina may shed light on differential caspase specificity in global cerebral ischemia.