Deletion of Puma protects hippocampal neurons in a model of severe status epilepticus.
Deletion of Puma protects hippocampal neurons in a model of severe status epilepticus.
复制标题
DOI：
10.1016/j.neuroscience.2010.03.057
复制
发表时间：
2010-06-30
期刊：
影响因子：
3.3
通讯作者：
Henshall, D. C.
中科院分区：
文献类型：
--
作者：
Engel, T.;Hatazaki, S.;Tanaka, K.;Prehn, J. H. M.;Henshall, D. C.
长时间的癫痫发作（癫痫持续状态）可以激活细胞凋亡相关的信号通路。这些通路对细胞死亡的影响程度可能取决于损伤强度，因此当癫痫发作更严重或持续时间较长时，程序性或凋亡性细胞死亡成分减少。我们最近发现，缺乏促凋亡Bcl-2同源结构域3-only蛋白Puma （Bbc3）的小鼠可以有效地保护其免受癫痫持续状态引起的损伤。在本研究中，我们研究了当癫痫发作更严重时，Puma缺乏是否具有保护作用。C57BL/6小鼠杏仁核内微注射1 μg kainic acid （KA）可触发癫痫持续状态，持续时间约为劳拉西泮终止前0.3 μg KA的两倍。高剂量组海马损伤也明显更大。通过末端脱氧核苷酸dUTP缺口末端标记（TUNEL）评估，癫痫发作后退化神经元DNA片段化阳性超过80%。tunel阳性细胞的神经元核形态显微镜分析显示，高剂量KA组显示大圆形凝聚染色质团块的比例比低剂量KA组低约50%。然而，与高剂量KA致癫痫持续状态的杂合子和野生型小鼠相比，puma缺陷小鼠海马中的神经元死亡减少了约50%。这些数据表明，癫痫诱发的神经元死亡的凋亡成分的各个方面是损伤持续时间或严重依赖。此外，他们提供了进一步的遗传证据，表明癫痫诱导的神经元死亡是可以通过靶向所谓的凋亡相关信号通路来预防的，而Puma缺失可能会破坏caspase不依赖或非凋亡的癫痫诱导的神经元死亡。
Prolonged seizures (status epilepticus) can activate apoptosis-associated signaling pathways. The extent to which such pathways contribute to cell death might depend on the insult intensity, whereby the programmed or apoptotic cell death component is reduced when seizures are more severe or protracted. We recently showed that mice lacking the pro-apoptotic Bcl-2 homology domain 3-only protein Puma (Bbc3) were potently protected against damage caused by status epilepticus. In the present study we examined whether Puma deficiency was protective when the seizure episode was more severe. Intra-amygdala microinjection of 1 μg kainic acid (KA) into C57BL/6 mice triggered status epilepticus that lasted about twice as long as with 0.3 μg KA prior to lorazepam termination. Hippocampal damage was also significantly greater in the higher-dose group. Over 80 % of degenerating neurons after seizures were positive for DNA fragmentation assessed by terminal deoxynucleotidyl dUTP nick end labeling (TUNEL). Microscopic analysis of neuronal nuclear morphology in TUNEL-positive cells revealed the proportion displaying large rounded clumps of condensed chromatin was ∼50 % lower in the high-dose versus low-dose KA group. Nevertheless, compared to heterozygous and wild-type mice subject to status epilepticus by high-dose KA, neuronal death was reduced by ∼50 % in the hippocampus of Puma-deficient mice. These data suggest aspects of the apoptotic component of seizure-induced neuronal death are insult duration- or severity-dependent. Moreover, they provide further genetic evidence that seizure-induced neuronal death is preventable by targeting so-called apoptosis-associated signaling pathways and Puma loss likely disrupts caspase-independent or non-apoptotic seizure-induced neuronal death.
登录
查看更多内容
影响因子：
4.8
作者：
Engel, Tobias;Murphy, Brona M.;Henshall, David C.
通讯作者：
Henshall, David C.
DOI：
10.1073/pnas.92.16.7162
发表时间：
1995-08-01
影响因子：
11.1
作者：
BONFOCO, E;KRAINC, D;LIPTON, SA
通讯作者：
LIPTON, SA
影响因子：
16.2
作者：
ANKARCRONA, M;DYPBUKT, JM;NICOTERA, P
通讯作者：
NICOTERA, P
DOI：
10.1097/00004647-199603000-00003
发表时间：
1996-03-01
影响因子：
6.3
作者：
Du, C;Hu, R;Choi, DW
通讯作者：
Choi, DW
DOI：
10.1016/s0169-328x(99)00143-6
发表时间：
1999-06-18
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Faherty, CJ;Xanthoudakis, S;Smeyne, RJ
通讯作者：
Smeyne, RJ