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

中风目前是未得到满足的最高医疗需求之一。尽管是致残的主要原因和死亡的五分之一，但目前只有一种药物获得批准。然而，30多个相关的禁忌症使85%的中风患者没有任何药物治疗。我发现氧化和硝化应激及其相互作用是中风后大脑损伤的主要原因。事实上，我验证了三个独立的靶点：NADPH氧化酶、一氧化氮合酶和cGMP形成酶sGC；它们分别可以被NOX抑制剂、NOS抑制剂和sGC激活剂安全地调节。尽管有神经保护作用，但在过去的几十年里，所有治疗中风的单一靶点方法都失败了。为了克服这种反复出现的“一靶一药”治疗失败，我提出了一种新的战略，即所谓的网络药理学。这种方法着眼于获得最大疗效和安全性的机械相关、协同靶点。因此，我将敏锐地检查几种协同作用，重点放在将治疗协同作用确立为最终目标的组合方法上。然而，治疗急性中风仍然不够。重要的是，30%的中风患者经历了残余的认知障碍。因此，我将使已经得到验证的急性网络药理学疗法适应于专注于中风后认知障碍的新的慢性框架。然而，ROS-cGMP信号网络也在其他不可治疗的与机制相关的认知障碍中受损，如血管性痴呆。此外，由于所有可能的候选因素都不够具体，因此现在都不可能通过生物标志物对患者进行分层或预测预后。因此，我建议将我在急性中风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、安全、有效和神经保护的治疗方法从急性脑缺血转化为中风后认知障碍和血管性痴呆，并结合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.