Melanis Konstantinos, Stefanou Maria-Ioanna, Themistoklis Konstantinos M, Papasilekas Themistoklis
Second Department of Neurology, School of Medicine and 'Attikon' University Hospital, National and Kapodistrian University of Athens, Rimini 1 Chaidari, Athens 12462, Greece.
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Ther Adv Neurol Disord. 2023 Aug 9;16:17562864231187770. doi: 10.1177/17562864231187770. eCollection 2023.
Stroke is ranked as the second leading cause of death worldwide and a major cause of long-term disability. A potential therapeutic target that could offer favorable outcomes in stroke is the mammalian target of rapamycin (mTOR) pathway. mTOR is a serine/threonine kinase that composes two protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and is regulated by other proteins such as the tuberous sclerosis complex. Through a significant number of signaling pathways, the mTOR pathway can modulate the processes of post-ischemic inflammation and autophagy, both of which play an integral part in the pathophysiological cascade of stroke. Promoting or inhibiting such processes under ischemic conditions can lead to apoptosis or instead sustained viability of neurons. The purpose of this review is to examine the pathophysiological role of mTOR in acute ischemic stroke, while highlighting promising neuroprotective agents such as hamartin for therapeutic modulation of this pathway. The therapeutic potential of mTOR is also discussed, with emphasis on implicated molecules and pathway steps that warrant further elucidation in order for their neuroprotective properties to be efficiently tested in future clinical trials.
中风是全球第二大死因,也是长期残疾的主要原因。哺乳动物雷帕霉素靶蛋白(mTOR)信号通路是一个有望为中风治疗带来良好疗效的潜在靶点。mTOR是一种丝氨酸/苏氨酸激酶,它构成两种蛋白复合物,即mTOR复合物1(mTORC1)和mTOR复合物2(mTORC2),并受结节性硬化复合物等其他蛋白的调控。通过大量信号通路,mTOR信号通路可调节缺血后炎症和自噬过程,这两者在中风的病理生理级联反应中均起着不可或缺的作用。在缺血条件下促进或抑制这些过程可导致神经元凋亡或维持其存活。本综述旨在探讨mTOR在急性缺血性中风中的病理生理作用,同时重点介绍如错构瘤蛋白等有前景的神经保护剂,用于对该信号通路进行治疗性调控。文中还讨论了mTOR的治疗潜力,重点关注那些需要进一步阐明的相关分子和信号通路步骤,以便在未来临床试验中有效测试它们的神经保护特性。