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

通过常见信号靶标的网络药理学对急性缺血性中风、中风后认知障碍和机械相关疾病进行一流的神经保护治疗

• 批准号: 449729893
• 负责人: Dr. Ana I. Casas Guijarro
• 金额: --
• 依托单位: Klinik für Neurologie
• 依托单位国家: 德国
• 项目类别: WBP Position
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/449729893?language=en
• 关键词: First; class; neuroprotective; therapy; acute

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.

中风目前是最未满足的医疗需求之一。尽管它是导致残疾的主要原因和五分之一的死亡原因，但目前只有一种药物获得批准。然而，超过 30 种相关禁忌症使得 85% 的中风患者无法接受任何药物治疗。我发现氧化应激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目标：NADPH 氧化酶、NO 合酶和 cGMP 形成酶 sGC；可以分别通过 NOX 抑制剂、NOS 抑制剂和 sGC 激活剂安全地调节。尽管具有神经保护作用，但在过去的几十年中，所有治疗中风的单靶点方法都失败了。为了克服这种反复出现的“单靶点、单一药物”治疗失败的情况，我提出了一种新的策略，即所谓的网络药理学。这种方法侧重于机械相关的协同目标，以实现最大功效和安全性。因此，我将敏锐地研究几种协同作用，重点关注组合方法，将治疗协同作用作为最终目标。然而，治疗急性中风仍然不够。重要的是，30% 的中风患者存在残余认知障碍。因此，我将采用已经验证的急性网络药理学疗法，以适应新的慢性框架，重点关注中风后认知障碍。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）中也会受损。此外，由于所有可能的候选者都不够具体，因此现在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的、安全的、有效的和神经保护性的治疗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。