Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. Thiamet G is a selective and potent inhibitor of O-GlcNAcase (OGA), which can remove O-GlcNAc from modified proteins, with Ki of 20 nM for human OGA[3]. In Pc-12 cells, Thiamet G increased the level of O-GlcNAc by inhibiting OGA with an EC50 value of 30 nM. Thiamet G (100 mM) decreased tau phosphorylation at Ser396, Thr231, Ser422, and Ser262 by 2.1, 2.7, 1.2, and 1.3 times, respectively. Thiamet G was injected intravenously at a dose of 50 mg/kg in rats. It could increase the O-GlcNAc level in brain in a dose- and time-dependent manner and reduce tau phosphorylation in brain after crossing the blood brain barrier[4].
Thiamet G 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Neuroblastoma N2a cells
5 µM
12 hours
Thiamet-G (TG), an OGA inhibitor, increased O-GlcNAcylation of N2a cells in a dose-dependent manner without affecting cell viability. TG treatment also inhibited H2O2-induced apoptosis in N2a cells.
Acta Pharmacol Sin. 2024 Apr;45(4):714-727.
BV2 cells
200 ng/mL
12 hours
To evaluate the effect of TMG on M1 polarization of BV2 cells. Results showed that TMG treatment inhibited LPS-induced M1 polarization and reduced mRNA expression of pro-inflammatory cytokines (TNF-α, iNOS, IL-1β, IL-6, and MCP-1).
To evaluate the effect of O-GlcNAcylation on autophagy in bladder cancer cells. Results showed that TG treatment increased O-GlcNAcylation and p62 levels and decreased LC3 II expression, indicating inhibition of autophagy.
Cell Mol Biol Lett. 2020 Mar 10;25:17.
5637 cells
10 µM
16 hours
To evaluate the effect of O-GlcNAcylation on autophagy in bladder cancer cells. Results showed that TG treatment increased O-GlcNAcylation and p62 levels and decreased LC3 II expression, indicating inhibition of autophagy.
Cell Mol Biol Lett. 2020 Mar 10;25:17.
Cartilage endplate stem cells (CESCs)
1 µM
21 days
Thiamet-G promoted osteogenic differentiation and inhibited chondrogenic differentiation of CESCs
Stem Cell Res Ther. 2019 Nov 28;10(1):357.
Human rheumatoid arthritis synovial fibroblasts (RASFs)
1-5 µM
24 hours
To evaluate the inhibitory effect of Thiamet G on IL-1β-induced IL-6 and IL-8 production, results showed that Thiamet G dose-dependently inhibited IL-1β-induced IL-6 and IL-8 production and increased the expression of O-GlcNAc-modified proteins.
Front Immunol. 2022 Aug 10;13:928436.
BeWo human trophoblast cells
5 µM
24 hours
TMG upregulated the expression of syncytiotrophoblast-associated transcription factors OVOL1 and GCM1 and the cell fusion gene ERVFRD1
Cells. 2020 Oct 6;9(10):2246.
Mouse blastocysts
5 µM
24 hours
TMG increased O-GlcNAcylation levels, altered OGT and OGA localization, and promoted mouse blastocyst invasion of endometrial epithelium
Cells. 2020 Oct 6;9(10):2246.
Human umbilical vein endothelial cells (HUVECs)
1 µM
24 hours
TMG pretreatment reduced GSDMD-N protein levels, indicating that TMG may function by inhibiting GSDMD cleavage
Inflamm Res. 2024 Jan;73(1):5-17.
HCT116 cells
1 µM
6 hours
To study the response of OGT intron retention to O-GlcNAc levels
Cell Rep. 2017 Aug 1;20(5):1088-1099.
293A-TOA cells
1 µM
6 hours
To study the response of OGT intron retention to O-GlcNAc levels
Cell Rep. 2017 Aug 1;20(5):1088-1099.
Primary mouse vascular smooth muscle cells (VSMC)
10 µM
6 hours
Increased O-GlcNAcylation and promoted VSMC calcification
Circ Res. 2014 Mar 28;114(7):1094-102.
HEK293 cells
32 nM (EC50)
6 hours
To evaluate the effect of Thiamet G on O-GlcNAcylated protein levels, showing a dose-dependent increase in O-protein levels.
Thiamet-G significantly reduced cell death in primary cortical neurons transfected with HTT 82Q and rescued nucleocytoplasmic trafficking defects with the nuclear restoration of both endogenous Ran and exogenous NLS-tdTomato-NES.
Neuron. 2017 Apr 5;94(1):93-107.e6
Mice
C57BL/6J mice
Intracranial injection
1 mM
Single injection
Injection of Thiamet G in the VTA and NAc facilitated neuronal O-GlcNAcylation and decreased the operant response to sucrose as well as the latency to fall in rotarod test.
Neurosci Bull. 2022 Mar;38(3):263-274
Rhesus monkeys
Rhesus monkeys and OgaΔBr mice
Intravenous injection
10 mg/kg
Single dose, PET scan performed 45 minutes after administration
To evaluate the inhibitory effect of Thiamet-G on OGA, results showed that Thiamet-G significantly reduced brain uptake of the radioligand, indicating high efficacy in inhibiting OGA.
J Nucl Med. 2019 Jan;60(1):129-134
NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice
Xenograft tumor model
Intraperitoneal injection
20 mg/kg
Once daily for 24 days
To study the effect of ISS deletion on tumor growth
Cell Rep. 2017 Aug 1;20(5):1088-1099.
Mice
Low-dose streptozotocin (STZ)-induced diabetic mouse model
Intravenous injection
20 mg/kg
Weekly for 2 months
Increased vascular O-GlcNAcylation, accelerated vascular calcification and worsened aortic compliance
Circ Res. 2014 Mar 28;114(7):1094-102.
C57BL/6 mice
Middle cerebral artery occlusion (MCAO) model
Intraperitoneal injection
20 mg/kg
Preventive group: once daily for 3 days before surgery; Therapeutic group: starting at 0.5 h after surgery, once daily for 3 days
To evaluate the neuroprotective effect of TMG in MCAO mice. Results showed that TMG significantly reduced infarct volume, improved neurological deficit scores, and modulated the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG reduced the number of Iba1+ cells, decreased expression of M1 markers, and increased expression of M2 markers.
Thiamet G restored REMSD-induced learning and memory impairment and dendritic spine density
Neurotherapeutics. 2021 Oct;18(4):2504-2517
Mice
Transient or permanent middle cerebral artery occlusion model
Intraperitoneal or intravenous injection
30 mg/kg
18 hours before or 30 minutes after stroke induction
Increased O-GlcNAcylation levels, improved stroke outcome in both young and aged mice
Stroke. 2017 Jun;48(6):1646-1654
Mice
Young mice (2-month-old)
Intraperitoneal injection
30 mg/kg/day
Once daily for 35 days
To mimic age-related elevation of O-GlcNAc and study its effect on spermatogenesis. Results showed that high O-GlcNAcylation led to decreased sperm concentration, reduced testis weight and organ index, and impaired spermatogenesis.
Cell Death Discov. 2023 May 15;9(1):163
RTg4510 mice
Tauopathy model
Oral
500 mg/kg/day
Daily administration for 8 weeks
To evaluate the effect of Thiamet G on tau pathology, showing that chronic Thiamet G treatment significantly reduced insoluble tau aggregates and phosphorylated tau species in the brain and decreased total tau levels in cerebrospinal fluid.
Mol Neurodegener. 2017 May 18;12(1):39.
C57BL/6J mice
LPS-induced sepsis model
Intravenous injection
600 μg/kg
Single dose, lasting 12 hours
TMG treatment increased blood perfusion in the liver, mesentery, and lower limbs of mice and reduced vascular endothelial injury
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