Scientific Research Institute of Neurosciences and Medicine (SRINM), Timakova Str. 4, Novosibirsk 630117, Russia.
Mental Health Research Center, Kashirskoye shosse 34, Moscow 115522, Russia.
Pharmacol Res. 2022 Sep;183:106373. doi: 10.1016/j.phrs.2022.106373. Epub 2022 Jul 28.
Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities.
自噬的诱导是治疗神经退行性疾病的一种有前景的方法。在最近的十年中，海藻糖引起了特别的关注。它是一种具有轻微副作用的自噬诱导剂，并且根据 FDA 的要求已被批准用于人类。海藻糖在各种疾病的实验模型中均具有治疗作用。这种具有灵活的α-1-1'-糖苷键的葡萄糖二糖具有独特的性质：诱导 mTOR 非依赖性自噬（以激酶 AMPK 为主要靶标）和对赋予其天然空间结构的蛋白质具有伴侣样作用。因此，它可以减少神经毒性异常/错误折叠蛋白的积累。海藻糖具有抗炎作用，并抑制有害的氧化应激，部分原因是增强了以 Nrf2 蛋白为代表的内源性抗氧化防御。该二糖通过 TFEB 和 FOXO1 等蛋白因子激活溶酶体和自噬体的生物发生途径。本文综述了海藻糖的神经保护作用的各种机制，并探讨了其多效性的可能性。讨论了有关海藻糖药效学的特定特征的最新知识。还检查了海藻糖在阿尔茨海默氏病、帕金森氏病和亨廷顿氏病等主要神经退行性疾病的动物模型中的神经保护作用。关注的焦点是将该药物向临床试验的转化，特别是口服和肠胃外给药途径。此外，还分析了通过 mTOR 依赖性和 mTOR 非依赖性自噬诱导剂的组合来增强治疗益处的可能性。总的来说，海藻糖似乎是一种很有前途的抑制实验性神经退行性变的多靶工具，需要对其临床能力进行彻底的研究。
