Tauskela Joseph S, Blondeau Nicolas
Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Road, Ottawa, ON K1A 0R6, Canada.
CNRS, IPMC, Université Côte d'Azur, Sophia Antipolis, F-06560 Valbonne, France.
Life (Basel). 2025 May 30;15(6):883. doi: 10.3390/life15060883.
All human clinical trials evaluating neuroprotective therapeutics in cerebral ischemia have failed, casting a pall over the field which has not recovered. Numerous methodological issues in the performance of these trials were identified, with the result that current trials are now subject to higher degrees of rigor and transparency. Advances in re-canalization technologies now offer the hope that adjunctive neuroprotection can improve patient outcome. The evaluation of neuroprotection in preclinical animal models has also suffered from methodological issues, which has also been addressed, resulting in an improved performance of studies. This leaves the question of how to actually pick the most appropriate neuroprotective therapy for translation. Given the current limitations in resources, and the numerous strategies that have been proposed to take advantage of clinical and preclinical methodological improvements, we suggest that in vitro studies involving subjecting the most sensitive cells-neurons-to oxygen-glucose deprivation (OGD) can be used to resolve among the many possibilities. Specifically, a large body of evidence shows that successive increases in OGD durations (spanning the lethal/supra-lethal continuum) require increasingly 'strong' drugs and combinations to adequately protect neurons (criteria not met in clinical trials). Notably, as the OGD duration is lengthened, NMDA receptor (NMDAR) antagonists of increasing potency and dose are required to match this increasing severity. Under supra-lethal OGD conditions, cocktails composed of anti-excitotoxic antagonists with maximal potency and dose are required to achieve neuroprotection. We propose that this approach can serve as a strategy-a neuroprotective framework-to prioritize among the many possibilities that exist for neuroprotective therapeutics for translation. Specifically, utilize the OGD continuum to compare within-, between- and outside-classes of drugs, first alone and then in combinations, to identify the most efficacious drugs ('head-to-head' competitions to identify the 'last man standing'). While the current state of knowledge strongly suggests that anti-excitotoxic approaches are required, this framework allows the integration of testing established and new therapeutics alike. This framework should include new technologies such as multi-electrode arrays (MEAs), which allow the evaluation of adverse effects of drugs alone, as well as if a drug truly provides functional neuroprotection, and not just survival. The neuroprotective framework provides a comprehensive strategy to eliminate ineffectual treatments, leaving only those modalities with the highest therapeutic index to be prioritized for translation.
所有评估脑缺血神经保护疗法的人体临床试验均告失败，给这个尚未恢复元气的领域蒙上了一层阴影。这些试验在实施过程中发现了诸多方法学问题，结果是当前的试验现在要遵循更高程度的严谨性和透明度。再灌注技术的进步如今带来了希望，即辅助性神经保护可改善患者预后。临床前动物模型中神经保护的评估也存在方法学问题，这些问题也已得到解决，研究表现有所改善。这就留下了一个问题，即如何实际挑选出最适合转化的神经保护疗法。鉴于目前资源有限，以及为利用临床和临床前方法学改进而提出的众多策略，我们建议涉及使最敏感细胞——神经元——经历氧糖剥夺（OGD）的体外研究可用于在众多可能性中做出抉择。具体而言，大量证据表明，OGD持续时间的连续增加（跨越致死/超致死连续体）需要越来越“强效”的药物及组合才能充分保护神经元（临床试验未达到这一标准）。值得注意的是，随着OGD持续时间延长，需要效力和剂量不断增加的N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂来应对这种不断增加的严重程度。在超致死OGD条件下，需要由具有最大效力和剂量的抗兴奋毒性拮抗剂组成的鸡尾酒疗法来实现神经保护。我们提出，这种方法可作为一种策略——一个神经保护框架——用于在神经保护疗法转化的众多可能性中确定优先次序。具体而言，利用OGD连续体来比较药物类别内部、类别之间以及类别之外的情况，首先单独比较，然后组合比较，以确定最有效的药物（“正面交锋”竞争以找出“最后胜出者”）。虽然目前的知识状况强烈表明需要采用抗兴奋毒性方法，但这个框架允许整合对既有疗法和新疗法的测试。这个框架应包括多电极阵列（MEA）等新技术，多电极阵列可单独评估药物的不良反应，以及评估一种药物是否真的能提供功能性神经保护，而不仅仅是细胞存活。神经保护框架提供了一个全面的策略，以淘汰无效的治疗方法，只留下那些治疗指数最高的疗法作为转化的优先选择。
