Disaccharide trehalose in experimental therapies for neurodegenerative disorders: Molecular targets and translational potential. (September 2022)

• Record Type: Journal Article
• Authors: Pupyshev, Alexander B.; Klyushnik, Tatyana P.; Akopyan, Anna A.; Singh, Sandeep Kumar; Tikhonova, Maria A.
• Is Part Of: Pharmacological research. Volume 183(2022)
• Publication Date: 2022-09
• Subjects: Aβ amyloid beta -- AD Alzheimer's disease -- Akt protein kinase B -- ALS amyotrophic lateral sclerosis -- АМРK AMP activated protein kinase -- APP amyloid precursor protein -- BAD BCL2 associated agonist of cell death -- Bcl-2 (B-cell lymphoma 2) regulator protein -- BAX a major member of the Bcl-2 family -- CAT catalase -- DA dopamine -- DAT dopamine transporter -- DOPAC 3, 4-dihydroxyphenylacetic acid -- FDA Food and Drug Administration -- GABA gamma-aminobutyric acid -- GFP green fluorescent protein -- GLUT glucose transporter -- GR glutathione reductase -- GSH glutathione peroxidase -- HD Huntington's disease -- HDAC histone deacetylase -- HO-1 heme oxygenase 1 -- HSP heat shock protein -- IL interleukin -- IV intravenous -- JNK1 c-Jun N-terminal kinase 1 -- LAMP lysosome-associated membrane protein -- LC3 microtubule-associated proteins 1A/1B light chain 3B -- MAPK mitogen-activated protein kinase -- mHtt mutant huntingtin -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- mTOR mammalian target of rapamycin -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- NQO1 NAD(P)H-quinone oxidoreductase 1 -- Nrf2 nuclear factor erythroid 2–related factor 2 -- OPMD oculopharyngeal muscular dystrophy -- PD Parkinson's disease -- PI3K phosphoinositide 3-kinase -- ROS reactive oxygen species -- SLC2A solute carrier family 2 (facilitated glucose transporter) -- SMERs small molecule enhancers of rapamycin -- SOD superoxide dismutase -- SQSTM1 sequestosome 1 -- TBP TATA-binding protein -- TFEB transcription factor EB -- TH tyrosine hydroxylase -- TNFα tumor necrosis factor α -- Tsc1/2 tuberous sclerosis complex 1/2 -- ULK1 Unc-51-like autophagy-activating kinase; Trehalose -- mTOR-independent autophagy -- Neurodegenerative disorder -- Neuroprotection -- Multitarget therapy -- Clinical trial; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106373
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: 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. Graphical Abstract: ga1 Highlights: Trehalose possesses multiple effects that are useful for neurodegeneration treatment. Trehalose induces mTOR-independent autophagy, seemingly without pleiotropic effect. Neuroprotective effect of trehalose is higher when combined with mTOR-dependent autophagy. Trehalose has beneficial therapeutic effect in various neurodegenerative models. Clinical trials of trehalose for neuroprotection are in progress.