Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus.
Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus.
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DOI：
10.3390/ijms18071502
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发表时间：
2017-07-12
影响因子：
5.6
通讯作者：
Anderson AE
中科院分区：
文献类型：
--
作者：
Lai YC;Baker JS;Donti T;Graham BH;Craigen WJ;Anderson AE
线粒体功能障碍在与癫痫持续状态（SE）相关的神经病理学中起着核心作用，并与癫痫的发展有关。虽然兴奋性毒性机制是影响SE后线粒体健康的众所周知的介质，但聚（ADP-核糖）聚合酶-1（PARP-1）的过度活化是否也有助于SE诱导的线粒体功能障碍仍有待研究。在这里，我们首先评估了在海人酸诱导的SE后海马中聚ADP核糖基化蛋白水平的时间演变作为PARP-1活性的标志物，并发现PARP-1在SE后24小时过度活跃。我们评估了氧化代谢，发现酶循环降低NAD+水平，并在SE后24 h通过极谱法测定受损NAD+依赖性线粒体呼吸。体视学估计显示显着的细胞损失海马CA 1和CA 3亚区后SE 72小时。使用N-（6-氧代-5，6-二氢-菲啶-2-基）- N，N-二甲基乙酰胺（PJ-34）体内给药的PARP-1抑制作用与NAD+水平和NAD+依赖性线粒体呼吸保持以及CA 1神经元存活改善相关。这些发现表明，PARP-1过度激活有助于SE相关的线粒体功能障碍和CA 1海马损伤。PARP-1超活化对线粒体呼吸的有害作用部分通过细胞内NAD+耗竭介导。因此，调节PARP-1活性可能是SE后保护细胞内能量和线粒体功能的潜在治疗靶点。
Mitochondrial dysfunction plays a central role in the neuropathology associated with status epilepticus (SE) and is implicated in the development of epilepsy. While excitotoxic mechanisms are well-known mediators affecting mitochondrial health following SE, whether hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) also contributes to SE-induced mitochondrial dysfunction remains to be examined. Here we first evaluated the temporal evolution of poly-ADP-ribosylated protein levels in hippocampus following kainic acid-induced SE as a marker for PARP-1 activity, and found that PARP-1 was hyperactive at 24 h following SE. We evaluated oxidative metabolism and found decreased NAD+ levels by enzymatic cycling, and impaired NAD+-dependent mitochondrial respiration as measured by polarography at 24 h following SE. Stereological estimation showed significant cell loss in the hippocampal CA1 and CA3 subregions 72 h following SE. PARP-1 inhibition using N-(6-Oxo-5,6-dihydro-phenanthridin-2-yl)- N,N-dimethylacetamide (PJ-34) in vivo administration was associated with preserved NAD+ levels and NAD+-dependent mitochondrial respiration, and improved CA1 neuronal survival. These findings suggest that PARP-1 hyperactivation contributes to SE-associated mitochondrial dysfunction and CA1 hippocampal damage. The deleterious effects of PARP-1 hyperactivation on mitochondrial respiration are in part mediated through intracellular NAD+ depletion. Therefore, modulating PARP-1 activity may represent a potential therapeutic target to preserve intracellular energetics and mitochondrial function following SE.
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影响因子：
3.4
作者：
Kovacs, R;Schuchmann, S;Heinemann, U
通讯作者：
Heinemann, U
影响因子：
2.2
作者：
Cock, HR;Tong, X;Walker, MC
通讯作者：
Walker, MC
影响因子：
11.2
作者：
Lewis, Darrell V.;Shinnar, Shlomo;Hesdorffer, Dale C.;Bagiella, Emilia;Bello, Jacqueline A.;Chan, Stephen;Xu, Yuan;MacFall, James;Gomes, William A.;Moshe, Solomon L.;Mathern, Gary W.;Pellock, John M.;Nordli, Douglas R., Jr.;Frank, L. Matthew;Provenzale, James;Shinnar, Ruth C.;Epstein, Leon G.;Masur, David;Litherland, Claire;Sun, Shumei
通讯作者：
Sun, Shumei
DOI：
10.1016/0013-4694(72)90177-0
发表时间：
1972-01-01
期刊：
ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY
影响因子：
--
作者：
RACINE, RJ
通讯作者：
RACINE, RJ
影响因子：
3.3
作者：
Liang, LP;Ho, YS;Patel, M
通讯作者：
Patel, M