Department of Physiology and Neuroscience, Department of Neurology, Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA.
Stroke. 2021 Aug;52(9):3033-3044. doi: 10.1161/STROKEAHA.121.032241. Epub 2021 Jul 22.
We search for ischemic stroke treatment knowing we have failed-intensely and often-to translate mechanistic knowledge into treatments that alleviate our patients' functional impairments. Lessons can be derived from our shared failures that may point to new directions and new strategies. First, the principle criticisms of both preclinical and clinical assessments are summarized. Next, previous efforts to develop single-mechanism treatments are reviewed. Finally, new definitions, novel approaches, and different directions are presented. In previous development efforts, the basic science and preclinical assessment of candidate treatments often lacked rigor and sufficiency; the clinical trials may have lacked power, rigor, or rectitude; or most likely both preclinical and clinical investigations were flawed. Single-target agents directed against specific molecular mechanisms proved unsuccessful. The term neuroprotection should be replaced as it has become ambiguous: protection of the entire neurovascular unit may be called cerebral cytoprotection or cerebroprotection. Success in developing cerebroprotection-either as an adjunct to recanalization or as stand-alone treatment-will require new definitions that recognize the importance of differential vulnerability in the neurovascular unit. Recent focus on pleiotropic multi-target agents that act via multiple mechanisms of action to interrupt ischemia at multiple steps may be more fruitful. Examples of pleiotropic treatments include therapeutic hypothermia and 3K3A-APC (activated protein C). Alternatively, the single-target drug NA-1 triggers multiple downstream signaling events. Renewed commitment to scientific rigor is essential, and funding agencies and journals may enforce quality principles of rigor in preclinical science. Appropriate animal models should be selected that are suited to the purpose of the investigation. Before clinical trials, preclinical assessment could include subjects that are aged, of both sexes, and harbor comorbid conditions such as diabetes or hypertension. With these new definitions, novel approaches, and renewed attention to rigor, the prospect for successful cerebroprotective therapy should improve.
我们寻找缺血性脑卒中的治疗方法，深知我们未能将机制知识转化为减轻患者功能障碍的治疗方法，这是一次深刻而又经常的失败。我们可以从共同的失败中吸取教训，这些教训可能为我们指明新的方向和策略。首先，总结了临床前和临床评估的主要批评意见。其次，回顾了以前开发单机制治疗方法的努力。最后，提出了新的定义、新的方法和不同的方向。在以前的开发工作中，候选治疗方法的基础科学和临床前评估往往缺乏严谨性和充分性；临床试验可能缺乏力量、严谨性或正直性；或者最有可能的是，临床前和临床研究都存在缺陷。针对特定分子机制的单靶标药物治疗未能取得成功。神经保护这个术语应该被取代，因为它已经变得模糊不清：对整个神经血管单元的保护可以称为脑保护或脑保护。要成功开发脑保护，无论是作为再通的辅助手段还是作为独立的治疗方法，都需要新的定义，认识到神经血管单元中差异易损性的重要性。最近对多靶点药物的关注越来越多，这些药物通过多种作用机制作用于多个缺血步骤，可能会更有成效。多靶点治疗的例子包括治疗性低温和 3K3A-APC（激活蛋白 C）。或者，单靶标药物 NA-1 触发多个下游信号事件。必须重新致力于科学严谨性，资助机构和期刊可能会强制执行严格的科学质量原则。应选择适合研究目的的适当动物模型。在临床试验之前，临床前评估可以包括年龄较大、性别不同且患有糖尿病或高血压等合并症的受试者。有了这些新的定义、新的方法和对严谨性的重新关注，成功的脑保护治疗的前景应该会有所改善。
