Targeting Parthanatos in Ischemic Stroke.
Targeting Parthanatos in Ischemic Stroke.
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DOI：
10.3389/fneur.2021.662034
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发表时间：
2021
影响因子：
3.4
通讯作者：
Dawson TM
中科院分区：
文献类型：
--
作者：
Koehler RC;Dawson VL;Dawson TM
甲状旁腺激素是一种细胞死亡信号通路，DNA过度氧化损伤导致多聚腺苷二磷酸核糖聚合酶(PARP)过度激活。然后，PARP产生大的聚(ADP-核糖)聚合物，诱导线粒体外膜释放凋亡诱导因子。在胞浆中，凋亡诱导因子与巨噬细胞移动抑制因子形成复合体，该复合体移位到细胞核中，在那里它降解DNA并导致细胞死亡。在文献综述中，我们确定了来自13个实验室的24篇文章，支持在遭受暂时性和永久性大脑中动脉闭塞(MCAO)的年轻雄性小鼠和大鼠中，副死胎所起的作用。研究人员基于使用9种不同的PARP抑制剂(19项研究)或PARP1基因缺失的小鼠(7项研究)得出的结论。多项研究表明，大脑中动脉阻塞后有4-6小时的治疗窗口。在年轻的雌性大鼠中，来自两个实验室的两项使用两种不同的PARP抑制剂的研究支持甲状旁腺素的作用，而来自一个实验室的两项研究不支持年轻的雌性PARP1缺失小鼠的作用。除了肝素以外，大量文献表明，PARP抑制剂可以通过干扰NF-κB转录，抑制基质金属蛋白酶-9的释放，限制血脑屏障损伤和出血性转化来减轻神经炎症。总体而言，大多数文献强烈支持PARP抑制剂具有神经保护作用的科学前提，即使大多数文献没有报告行为结果或解决随机和治疗隐藏的问题。几种第三代PARP抑制剂进入临床肿瘤学试验，没有重大不良反应，可以用于中风。在进入中风临床试验之前，对老年动物或患有合并症的动物进行评估将是重要的。
Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor from the outer mitochondrial membrane. In the cytosol, apoptosis-inducing factor forms a complex with macrophage migration inhibitory factor that translocates into the nucleus where it degrades DNA and produces cell death. In a review of the literature, we identified 24 publications from 13 laboratories that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO). Investigators base their conclusions on the use of nine different PARP inhibitors (19 studies) or PARP1-null mice (7 studies). Several studies indicate a therapeutic window of 4–6 h after MCAO. In young female rats, two studies using two different PARP inhibitors from two labs support a role for parthanatos, whereas two studies from one lab do not support a role in young female PARP1-null mice. In addition to parthanatos, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NF-κB transcription, suppressing matrix metaloproteinase-9 release, and limiting blood-brain barrier damage and hemorrhagic transformation. Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective, even when most did not report behavior outcomes or address the issue of randomization and treatment concealment. Several third-generation PARP inhibitors entered clinical oncology trials without major adverse effects and could be repurposed for stroke. Evaluation in aged animals or animals with comorbidities will be important before moving into clinical stroke trials.
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影响因子：
8.3
作者：
Bosetti F;Koenig JI;Ayata C;Back SA;Becker K;Broderick JP;Carmichael ST;Cho S;Cipolla MJ;Corbett D;Corriveau RA;Cramer SC;Ferguson AR;Finklestein SP;Ford BD;Furie KL;Hemmen TM;Iadecola C;Jakeman LB;Janis S;Jauch EC;Johnston KC;Kochanek PM;Kohn H;Lo EH;Lyden PD;Mallard C;McCullough LD;McGavern LM;Meschia JF;Moy CS;Perez-Pinzon MA;Ramadan I;Savitz SI;Schwamm LH;Steinberg GK;Stenzel-Poore MP;Tymianski M;Warach S;Wechsler LR;Zhang JH;Koroshetz W
通讯作者：
Koroshetz W
影响因子：
3.2
作者：
Bakondi, E;Bai, P;Virág, L
通讯作者：
Virág, L
影响因子：
8.3
作者：
Alkayed, NJ;Murphy, SJ;Hurn, PD
通讯作者：
Hurn, PD
影响因子：
4.7
作者：
Chiarugi, A;Moskowitz, MA
通讯作者：
Moskowitz, MA
影响因子：
5.3
作者：
Eliasson, MJL;Huang, ZH;Moskowitz, MA
通讯作者：
Moskowitz, MA