Description
Thiamet G (1009816-48-1) is a potent, selective inhibitor of O-GlcNAcase (Ki?= 21 nM for human O-GlcNAcase). Increases levels of O-GlcNAc-modified proteins in cellular assays and?in vivo. Suppresses phosphorylation of tau protein in rat cortex and hippocampus.1?Stabilizes tau against aggregation and slows neurodegeneration.2?Thiamet G prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.3?Elevates soluble tau species and reduces tauopathy in mouse models.4?Active?in vivo?and blood brain barrier permeable.
Uses
As a potent O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo, The authors anticipate that Thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological
Biochem/physiol Actions
Thiamet G is a potent inhibitor of the enzyme O-GlcNAcase (Ki = 21 nM). The compound is orally bioavailable and crosses the blood brain barrier. Thiamet G leads to an increase in O-GlcNAc-modified proteins in cell-based and in vivo assay systems, and reduces levels of phosphorylated Tau protein in rat cortex and hippocampus.
in vivo
Thiamet G (500 mg/kg/d) increases global and tau O-GlcNAc and reduces neurodegeneration. Thiamet G-treated group has 1.4-fold more motor neurons and hinders tau-driven neurodegeneration within this transgenic model. Thiamet G treatment therefore has no detectable effect on mice lacking the P301L transgene, indicating that prevention of neurodegeneration and weight loss is mediated by Thiamet G treatment only in the context of the P301L transgene. In Thiamet G-treated mice, the O-GlcNAc increases in the brain and spinal cord tissues[1].
Thiamet G (20 mg/kg, i.p.) increases O-GlcNAc levels in brain, liver, and knee of the C57BL/6 mice in a dose-dependent manner[2].
References
1) Yuzwa?et al. (2008),?A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo; Nat. Chem. Biol.,?4?483
2) Yuzwa?et al. (2012),?Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation; Nat. Chem. Biol.?8?393
3) Yuzwa?et al. (2014),?Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice; Mol. Neurodegener.,?9?42
4) Hastings?et al.?(2017)?Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice;?Mol. Neurodegener.,?12?39
