Koehler Raymond C, Dawson Valina L, Dawson Ted M
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, United States.
Neuroregeneration and Stem Cell Programs, The Institute of Cell Engineering, The Johns Hopkins University, Baltimore, MD, United States.
Front Neurol. 2021 May 5;12:662034. doi: 10.3389/fneur.2021.662034. eCollection 2021.
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.
PARP 过度激活介导的细胞死亡是一种细胞死亡信号通路，其中 DNA 的过度氧化损伤会导致聚（ADP - 核糖）聚合酶（PARP）过度激活。然后，PARP 会促使大量聚（ADP - 核糖）聚合物形成，从而诱导凋亡诱导因子从线粒体外膜释放。在细胞质中，凋亡诱导因子与巨噬细胞迁移抑制因子形成复合物，该复合物转移至细胞核，在细胞核中降解 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 篇出版物，这些文献支持 PARP 过度激活介导的细胞死亡在接受短暂和永久性大脑中动脉闭塞（MCAO）的年轻雄性小鼠和大鼠中发挥作用。研究人员的结论基于使用九种不同的 PARP 抑制剂（19 项研究）或 PARP1 基因敲除小鼠（7 项研究）。多项研究表明，MCAO 后 4 - 6 小时存在治疗窗口期。在年轻雌性大鼠中，两项来自两个实验室、使用两种不同 PARP 抑制剂的研究支持 PARP 过度激活介导的细胞死亡发挥作用，而来自一个实验室的两项研究则不支持 PARP1 基因敲除的年轻雌性小鼠中存在这一作用。除了 PARP 过度激活介导的细胞死亡外，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 的释放以及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这一科学前提，即 PARP 抑制剂具有神经保护作用，即使大多数文献未报告行为结果或未涉及随机化和治疗隐匿问题。几种第三代 PARP 抑制剂已进入临床肿瘤学试验且无重大不良反应，可重新用于治疗中风。在进入临床中风试验之前，对老年动物或患有合并症的动物进行评估将非常重要。
