First-in-class neuroprotective therapy in acute ischemic stroke, poststroke cognitive impairment and mechanistically related diseases by network pharmacology of common signalling targets

中风目前是最高的未满足的医疗需求之一。尽管它是残疾的主要原因和死亡率的五分之一，但目前只有一种药物获得批准。然而，超过30种相关的禁忌症使85%的中风患者没有任何药物治疗。我确定氧化和硝化应激及其相互作用是中风后脑损伤的主要原因。事实上，我验证了三个独立的靶点：NADPH氧化酶、NO合酶和cGMP形成酶sGC;它们可以分别被NOX抑制剂、NOS抑制剂和sGC激活剂安全地调节。尽管它们具有神经保护作用，但在过去几十年中，中风的所有单靶点方法都失败了。为了克服这种反复出现的“一靶点，一药”治疗失败，我提出了一种新的策略，所谓的网络药理学。这种方法侧重于实现最大疗效和安全性的机制相关的协同靶标。因此，我将敏锐地研究几个协同作用，重点是建立治疗协同作用的最终目标的组合方法。然而，治疗急性中风仍然不够。重要的是，30%的中风患者经历残余认知障碍。因此，我将调整一个已经验证的急性网络药理学治疗，以一个新的慢性框架，重点是中风后认知障碍。然而，ROS-cGMP信号网络在其他不可治疗的机制相关认知障碍（即血管性痴呆）中也受损。此外，患者分层或通过生物标志物预测预后目前都是不可能的，因为所有可能的候选人都不够特异。因此，我建议将我在急性卒中治疗和网络药理学方面的工作扩展到不同的神经血管和认知障碍场景，以便将第一个广泛适用的，安全的，有效的神经保护治疗从急性脑缺血转化为卒中后认知障碍和血管性痴呆，并提供有效的生物标志物识别策略。

Stroke currently represents one of the highest unmet medical needs. Despite being the primary cause of disability and fifth of mortality, only one single drug is currently approved. However, more than 30 associated contraindications leaves 85% of all stroke patients without any pharmacotherapy. I identified oxidative and nitrative stress and their interaction as a major cause of brain damage post-stroke. In fact, I validated three independent targets: NADPH oxidase, NO synthase and the cGMP forming enzyme, sGC; which could be safely modulated by NOX inhibitors, NOS inhibitors and sGC activators, respectively. Despite their neuroprotective effect, all single target approaches in stroke failed during the last decades. To overcome this recurrent “one-target, one-drug” therapeutic failure, I propose a novel strategy so-called network pharmacology. This approach focusses on mechanistically-related, synergistic targets achieving both maximal efficacy and safety. Thus, I will acutely examine several synergies focusing on combinatory approaches establishing therapeutic synergy as the ultimate goal. However, treating acute stroke remains insufficient. Importantly, 30% of stroke patients experience residual cognitive impairment. Therefore, I will adapt an already validated acute network pharmacology therapy to a new chronic frame focused on post-stroke cognitive impairment. However, the ROS-cGMP signaling network is also impaired in other non-treatable mechanism-related cognitive disorders, i.e. vascular dementia. Additionally, neither patient stratification or predictive prognosis through biomarkers are nowadays possible since all possible candidates are not sufficiently specific. Therefore, I suggest to expand my work on acute stroke therapy and network pharmacology to different neurovascular and cognitive impaired scenarios in order to translate the first broadly applicable, safe, effective and neuroprotective therapy from acute brain ischemia to post-stroke cognitive impairment and vascular dementia together with a potent biomarker identification strategy.