Key Laboratory of Efficacy Evaluation of New Drug Candidate, Liaoning Province; Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Pharmacol Ther. 2024 Nov;263:108721. doi: 10.1016/j.pharmthera.2024.108721. Epub 2024 Sep 14.
Ischaemic stroke (IS) is the second leading cause of death and a major cause of disability worldwide. Currently, the clinical management of IS still depends on restoring blood flow via pharmacological thrombolysis or mechanical thrombectomy, with accompanying disadvantages of narrow therapeutic time window and risk of haemorrhagic transformation. Thus, novel pathophysiological mechanisms and targeted therapeutic candidates are urgently needed. The autophagy-lysosomal pathway (ALP), as a dynamic cellular lysosome-based degradative process, has been comprehensively studied in recent decades, including its upstream regulatory mechanisms and its role in mediating neuronal fate after IS. Importantly, increasing evidence has shown that IS can lead to lysosomal dysfunction, such as lysosomal membrane permeabilization, impaired lysosomal acidity, lysosomal storage disorder, and dysfunctional lysosomal ion homeostasis, which are involved in the IS-mediated defects in ALP function. There is tightly regulated crosstalk between transcription factor EB (TFEB), mammalian target of rapamycin (mTOR) and lysosomal function, but their relationship remains to be systematically summarized. Notably, a growing body of evidence emphasizes the benefits of naturally derived compounds in the treatment of IS via modulation of ALP function. However, little is known about the roles of natural compounds as modulators of lysosomes in the treatment of IS. Therefore, in this context, we provide an overview of the current understanding of the mechanisms underlying IS-mediated ALP dysfunction, from a lysosomal perspective. We also provide an update on the effect of natural compounds on IS, according to their chemical structural types, in different experimental stroke models, cerebral regions and cell types, with a primary focus on lysosomes and autophagy initiation. This review aims to highlight the therapeutic potential of natural compounds that target lysosomal and ALP function for IS treatment.
缺血性脑卒中（IS）是全球范围内第二大致死原因和主要致残原因。目前，IS 的临床治疗仍然依赖于通过药理学溶栓或机械取栓来恢复血流，但其伴随的治疗时间窗狭窄和出血转化风险等缺点。因此，迫切需要新的病理生理机制和靶向治疗候选物。自噬溶酶体途径（ALP）作为一个动态的细胞溶酶体降解过程，在最近几十年得到了全面研究，包括其上游调节机制及其在 IS 后介导神经元命运中的作用。重要的是，越来越多的证据表明，IS 可导致溶酶体功能障碍，如溶酶体膜通透性增加、溶酶体酸度受损、溶酶体储存障碍和功能失调的溶酶体离子稳态，这些都与 IS 介导的 ALP 功能缺陷有关。转录因子 EB（TFEB）、哺乳动物雷帕霉素靶蛋白（mTOR）和溶酶体功能之间存在着严格调控的串扰，但它们之间的关系仍有待系统总结。值得注意的是，越来越多的证据强调了天然化合物通过调节 ALP 功能在治疗 IS 中的益处。然而，关于天然化合物作为 IS 治疗中溶酶体调节剂的作用知之甚少。因此，在这种情况下，我们从溶酶体的角度概述了目前对 IS 介导的 ALP 功能障碍机制的理解。我们还根据其化学结构类型，在不同的实验性中风模型、脑区和细胞类型中，更新了天然化合物对 IS 的影响，主要关注溶酶体和自噬起始。本综述旨在强调针对溶酶体和 ALP 功能的天然化合物在 IS 治疗中的治疗潜力。
