Caspase-mediated death of newly formed neurons in the adult rat dentate gyrus following status epilepticus
Caspase-mediated death of newly formed neurons in the adult rat dentate gyrus following status epilepticus
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DOI：
10.1046/j.1460-9568.2002.02202.x
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发表时间：
2002-10-01
影响因子：
3.4
通讯作者：
Lindvall, O
中科院分区：
文献类型：
--
作者：
Ekdahl, CT;Mohapel, P;Lindvall, O
在正常条件下或响应脑损伤时在成人齿状回中增殖的大部分细胞仅表现出短期存活。在这里，我们试图确定哪些细胞死亡途径与电诱导癫痫持续状态 2 小时后大鼠齿状回中新形成的神经元的退化有关。我们研究了半胱氨酸蛋白酶、半胱天冬酶、钙蛋白酶和组织蛋白酶这三个家族的作用，它们都可以参与细胞凋亡。癫痫持续状态增加了齿状回颗粒下区溴脱氧尿苷（BrdU）阳性增殖细胞的数量。在细胞增殖最大时，免疫组织化学分析显示，大约 66% 的 BrdU 阳性细胞表达活性 caspase 裂解的聚（ADP-核糖）聚合酶 (PARP)，而它们均不表达组织蛋白酶 B 或 150 kDa 钙蛋白酶产生的胞质蛋白分解产物。为了评估半胱氨酸蛋白酶在调节新形成的神经元存活中的重要性，我们在癫痫损伤后 1 周开始，在两周内脑室内注射 caspase 抑制剂混合物（zVAD-fmk、zDEVD-fmk 和 zLEHD-fmk），足以允许神经元分化。在 caspase 抑制剂处理的大鼠的颗粒下区和颗粒细胞层中检测到用 BrdU 和神经元特异性核蛋白 (NeuN) 标记物双标记的细胞数量增加。我们的数据表明，半胱天冬酶介导的细胞死亡途径在癫痫持续状态产生的祖细胞后代中活跃，并在神经元分化过程中损害存活。
A large proportion of cells that proliferate in the adult dentate gyrus under normal conditions or in response to brain insults exhibit only short-term survival. Here, we sought to determine which cell death pathways are involved in the degeneration of newly formed neurons in the rat dentate gyrus following 2 h of electrically induced status epilepticus. We investigated the role of three families of cysteine proteases, caspases, calpains, and cathepsins, which can all participate in apoptotic cell death. Status epilepticus increased the number of bromodeoxyuridine (BrdU)-positive proliferated cells in the subgranular zone of the dentate gyrus. At the time of maximum cell proliferation, immunohistochemical analyses revealed protein expression of active caspase-cleaved poly (ADP-ribose) polymerase (PARP) in approximate to 66% of the BrdU-positive cells, while none of them expressed cathepsin B or the 150-kDa calpain-produced fodrin breakdown product. To evaluate the importance of cysteine proteases in regulating survival of the newly formed neurons, we administered intracerebroventricular infusions of a caspase inhibitor cocktail (zVAD-fmk, zDEVD-fmk and zLEHD-fmk) over a 2-week period, sufficient to allow for neuronal differentiation, starting 1 week after the epileptic insult. Increased numbers of cells double-labelled with BrdU and neuron-specific nuclear protein (NeuN) marker were detected in the subgranular zone and granule cell layer of the caspase inhibitor-treated rats. Our data indicate that caspase-mediated cell death pathways are active in progenitor cell progeny generated by status epilepticus and compromise survival during neuronal differentiation.