Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, United States.
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, United States.
Pharmacol Res. 2018 Oct;136:121-132. doi: 10.1016/j.phrs.2018.09.001. Epub 2018 Sep 8.
To minimize irreversible brain injury after acute ischemic stroke (AIS), the time to treatment (i.e., treatment delay) should be minimized. However, thus far, all cytoprotective clinical trials have failed. Analysis of literature identified short treatment durations (≤72 h) as a common motif among completed cytoprotective clinical trials. Here, we argue that short cytoprotective regimens even if given early after AIS may only slow down the evolution of ischemic brain injury and fail to deliver sustained long-term solutions leading to relapses that may be misinterpreted for conceptual failure of cytoprotection. In this randomized blinded study, we used young adult male rats subjected to transient 90 min suture middle cerebral artery occlusion (MCAO) and treated with acute vs. sub-chronic regimens of PNU120596, a prototypical positive allosteric modulator of α7 nicotinic acetylcholine receptors with anti-inflammatory cytoprotective properties to test the hypothesis that insufficient treatment durations may reduce therapeutic benefits of otherwise efficacious cytoprotectants after AIS. A single acute treatment 90 min after MCAO significantly reduced brain injury and neurological deficits 24 h later, but these effects vanished 72 h after MCAO. These relapses were avoided by utilizing sub-chronic treatments. Thus, extending treatment duration augments therapeutic efficacy of PNU120596 after MCAO. Furthermore, sub-chronic treatments could offset the negative effects of prolonged treatment delays in cases where the acute treatment window after MCAO was left unexploited. We conclude that a combination of short treatment delays and prolonged treatment durations may be required to maximize therapeutic effects of PNU120596, reduce relapses and ensure sustained therapeutic efficacy after AIS. Similar concepts may hold for other cytoprotectants including those that failed in clinical trials.
为了最大限度地减少急性缺血性脑卒中（AIS）后的不可逆性脑损伤，应尽量缩短治疗时间（即治疗延迟）。然而，迄今为止，所有的细胞保护临床试验都失败了。对文献的分析确定了较短的治疗持续时间（≤72 小时）是已完成的细胞保护临床试验的一个共同特征。在这里，我们认为即使在 AIS 后早期给予短时间的细胞保护方案，也可能只是减缓缺血性脑损伤的进展，并不能提供持续的长期解决方案，导致复发，这可能被误解为细胞保护概念上的失败。在这项随机、双盲研究中，我们使用年轻成年雄性大鼠进行短暂的 90 分钟缝线大脑中动脉闭塞（MCAO），并使用急性与亚慢性 PNU120596 方案治疗，PNU120596 是一种典型的α7 烟碱型乙酰胆碱受体正变构调节剂，具有抗炎细胞保护特性，以测试以下假设：治疗持续时间不足可能会降低 AIS 后 otherwise efficacious cytoprotectants 的治疗益处。MCAO 后 90 分钟单次急性治疗可显著降低 24 小时后的脑损伤和神经功能缺损，但这些效果在 MCAO 后 72 小时消失。通过利用亚慢性治疗避免了这些复发。因此，延长治疗时间可增强 PNU120596 治疗 MCAO 的疗效。此外，在 MCAO 后急性治疗窗口未被利用的情况下，亚慢性治疗可以抵消延长治疗延迟的负面影响。我们得出结论，为了最大限度地提高 PNU120596 的治疗效果，减少复发并确保 AIS 后的持续治疗效果，可能需要结合短的治疗延迟和长的治疗持续时间。其他细胞保护剂（包括临床试验失败的那些）也可能存在类似的概念。
