In male human-tau441 transgenic mice, a single intracerebroventricular dose of 175 µg Thiamet G increased brain O-GlcNAc but produced bidirectional tau phosphorylation responses. At 9 hours, Thr181 and Ser214 phosphorylation decreased, whereas Ser199, Ser396 and Ser422 increased. Total tau was unchanged. These acute central-administration findings do not establish uniform tau dephosphorylation. [2]
In male mice with established pressure overload, Thiamet G (20 mg/kg/day intraperitoneally for 2 weeks, starting 4 weeks after TAC) increased cardiac CPT1 activity and decreased PDH activity versus vehicle. Increased RL2-associated recovery of these proteins accompanied the activity changes, while total protein levels were not significantly altered. The results support model-specific metabolic effects without establishing improved cardiac function. [3]
Bidirectional tau phosphorylation after acute brain administration
Animal study · Male ~6-month-old human tau441 transgenic mice [2]
Acute brain dosing increased O-GlcNAc but did not uniformly suppress tau phosphorylation. At 9 hours, Thr181 and Ser214 decreased while Ser199, Ser396 and Ser422 increased. Thr217 was not significantly altered across the tested times. GSK-3β/AKT phosphorylation changes support a proposed kinase contribution, not proof of direct kinase inhibition by Thiamet-G.
Conditions shared by the study groups
- Route
- Intracerebroventricular, bilateral lateral-ventricle injection
- Frequency
- Single administration
- Treatment course
- Brain measurements at 4.5, 9 and 24 hours
- Vehicle
- 0.9% NaCl
- Thiamet-G versus saline
- Model: Male ~6-month-old tau441 transgenic mice expressing the largest wild-type human tau isoform
- Reported limits: No clinical or systemic-exposure inference. The paper estimates brain concentration from volume assumptions; that estimate is not an exposure measurement and is not adopted.
Methods and source locations
Compound reported in the paper: Thiamet-G; Compound label in the paper: Thiamet-G
Literature findings for Thiamet-G in the stated model and assay; no supplier-lot or clinical efficacy claim.
Figures 1–3 and captions; Results, site-specific changes of tau phosphorylation and activation of GSK-3β; Methods, Animals and Intracerebroventricular (icv) Injection and Western Blot Analysis
Brain global O-GlcNAc: RL2 immunoblots normalized to GAPDH; author-reported fold descriptions, not decimal values inferred from bars. — Figure 1B–C; Results, Thiamet-G increases protein O-GlcNAcylation level in the brain
Tau phosphorylation and total tau: Site-specific immunoblotting normalized to total tau (92e); Figure 2 mean ± SEM, n=5, *p<0.05 versus saline. — Figure 2A–D and corresponding Results paragraph
Kinase phosphorylation markers: Phosphorylated/total kinase immunoblot ratios; mean ± SEM, n=5; kinase activation is an interpretation from markers. — Figure 3A–B and corresponding Results paragraph
Thiamet-G versus saline · Methods, Animals and Intracerebroventricular (icv) Injection; Figures 1–3 and captions
Cardiac metabolic enzyme responses during established pressure overload
Animal study · Male C57BL/6J mice with established TAC-induced pressure overload; heart lysate endpoints [3]
The TMG-TAC group had increased CPT1 activity and decreased PDH activity compared with vehicle-TAC controls. RL2 immunoprecipitation recovered more CPT1B and PDH subunits while input protein levels were not significantly different. These associations do not identify a causal glycosylation site or demonstrate improved cardiac function. Systemic O-GlcNAc perturbation also limits attribution to a cardiac-intrinsic mechanism.
Conditions shared by the study groups
- Route
- Intraperitoneal
- Frequency
- Once daily
- Treatment course
- 2 weeks, beginning 4 weeks after TAC
- Vehicle
- Dimethyl sulfoxide (approximately 20 µL)
- TMG-TAC versus V-TAC
- Model: Male C57BL/6J mice, 3–5 months old, with established transverse-aortic-constriction pressure overload
- Reported limits: No exact activity mean ± SEM is tabulated in the adopted passages; none is estimated from the plotted points.
Methods and source locations
Compound reported in the paper: Thiamet-G; Compound label in the paper: TMG
Literature findings for Thiamet-G in the stated model and assay; no supplier-lot or clinical efficacy claim.
Figures 4D–F, 5, 6D–K and 7; Methods, Mice, Experimental set-up, Thiamet-G (TMG), IP, CPT1/PDH activity assays and Data visualization and statistical analysis; Discussion, Limitations: systemic TMG effects, male-only sampling and lack of site specificity
Cardiac CPT1 activity: Thiolytic cleavage assay with Triton X-100 subtraction; activity defined as nmol CoA-SH released/min/mg protein. Plots show mean ± SEM; unpaired two-tailed Student t-test. — Figure 5 and caption; Methods, CPT1 enzyme activity assay and Data visualization and statistical analysis
Cardiac PDH activity: PDH enzyme assay monitoring absorbance at 450 nm; activity defined as nmol NADH released/min/mg protein. Plots show mean ± SEM; unpaired two-tailed Student t-test. — Figure 7 and caption; Methods, PDH enzyme activity assay and Data visualization and statistical analysis
RL2-associated protein recovery and input controls: RL2 immunoprecipitation and immunoblots; normalization described in IP methods; plotted mean ± SEM. These are protein-association/O-GlcNAc enrichment measurements, not site-specific modification stoichiometry. — Figure 4D–F; Figure 6D–K and captions
TMG-TAC versus V-TAC · Methods, Experimental set-up and Thiamet-G (TMG); Figures 4D–F, 5, 6D–K and 7
