Loss of p53 results in protracted electrographic seizures and development of an aggravated epileptic phenotype following status epilepticus.
Loss of p53 results in protracted electrographic seizures and development of an aggravated epileptic phenotype following status epilepticus.
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DOI：
10.1038/cddis.2010.55
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发表时间：
2010-10-07
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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p53抑癌基因是一种多功能蛋白，可调控细胞周期、分化、DNA修复和凋亡。实验性癫痫发作上调脑中的p53，急性癫痫诱导的神经元死亡可以通过基因缺失或药物抑制p53来减少。然而，很少有长期的功能性后果的p53缺陷已被探讨。在这里，我们调查了野生型和p53缺陷小鼠癫痫持续状态引发癫痫的发展。对杏仁核内注射海人酸（KA）诱导的癫痫持续状态期间的脑电图（EEG）记录进行分析，结果表明，与野生型动物相比，p53缺陷小鼠的癫痫发作持续时间明显更长。然而，在海马CA3区和新皮质的神经元死亡显着减少，在72小时的p53基因缺陷小鼠。癫痫持续状态后的长期连续EEG遥测记录确定，与野生型小鼠相比，p53缺陷小鼠自发性癫痫发作的总持续时间显着延长。海马损伤和神经肽Y分布在慢性记录结束时被发现是p53缺陷和野生型小鼠之间的相似。本研究确定了长期KA诱导的电图状态作为p53缺陷的一种新的结果，并表明p53的缺乏导致癫痫表型加重。因此，靶向p53以保护免受癫痫持续状态或相关神经损伤可能会被癫痫发生期间或慢性癫痫中p53功能降低的有害后果所抵消。
The p53 tumor suppressor is a multifunctional protein, which regulates cell cycle, differentiation, DNA repair and apoptosis. Experimental seizures up-regulate p53 in the brain, and acute seizure-induced neuronal death can be reduced by genetic deletion or pharmacologic inhibition of p53. However, few long-term functional consequences of p53 deficiency have been explored. Here, we investigated the development of epilepsy triggered by status epilepticus in wild-type and p53-deficient mice. Analysis of electroencephalogram (EEG) recordings during status epilepticus induced by intra-amygdala kainic acid (KA) showed that seizures lasted significantly longer in p53-deficient mice compared with wild-type animals. Nevertheless, neuronal death in the hippocampal CA3 subfield and the neocortex was significantly reduced at 72 h in p53-deficient mice. Long-term continuous EEG telemetry recordings after status epilepticus determined that the sum duration of spontaneous seizures was significantly longer in p53-deficient compared with wild-type mice. Hippocampal damage and neuropeptide Y distribution at the end of chronic recordings was found to be similar between p53-deficient and wild-type mice. The present study identifies protracted KA-induced electrographic status as a novel outcome of p53 deficiency and shows that the absence of p53 leads to an exacerbated epileptic phenotype. Accordingly, targeting p53 to protect against status epilepticus or related neurologic insults may be offset by deleterious consequences of reduced p53 function during epileptogenesis or in chronic epilepsy.
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DOI：
10.1016/s0169-328x(98)00285-x
发表时间：
1999-01-08
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Liu, W;Rong, YQ;Schreiber, SS
通讯作者：
Schreiber, SS
影响因子：
4.8
作者：
Engel, Tobias;Murphy, Brona M.;Henshall, David C.
通讯作者：
Henshall, David C.
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
2.2
作者：
Pitkänen, A;Kharatishvili, I;Nissinen, J
通讯作者：
Nissinen, J
DOI：
10.1016/s0169-328x(01)00197-8
发表时间：
2001-09-30
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Djebaïli, M;Lerner-Natoli, M;Rondouin, G
通讯作者：
Rondouin, G