TDZD-8 is the first non-ATP competitive inhibitor of GSK-3β with IC50 value of 2μM. Pretreatment with TDZD-8 at 10μM for 1h showed neuroprotection against 6-OHDA-induced damage, shown by reduced cell death and apoptosis, in both SH-SY5Y cells and cultured CGNs. Intrahippocampal delivery of TDZD-8 blocked dephosphorylation and activation of GSK3β in db/db mice. This inhibition of GSK3β prevented accumulation of pS202Tau and hyperphosphorylation of pS396/404Tau in db/db mice. It also reduced somatodendritic tau phosphorylation in db/db mice. The normalization of spatial recognition memory in db/db mice and block of deficits in novel object study could also be observed. Recent study found that TDZD-8 showed inhibition effect on 2019-nCoV.
作用机制
TDZD-8 is a non-ATP competitive GSK-3β inhibitor.
TDZD-8 细胞实验
Cell Line
Concentration
Treated Time
Description
References
murine podocytes
5µM
24 h
TDZD-8 inhibited GSK3 β, reduced LPS-induced RelA/p65 phosphorylation at serine 467, ameliorated podocyte injury, but did not affect Bcl-xL expression or sensitize apoptosis.
Kidney Int. 2015 Jun;87(6):1176-90.
tubular epithelial cells (TKPT)
5, 10, 20 μM
24 h
TDZD-8 significantly improved the survival rate of DCLF-stimulated TKPT cells, suppressed apoptosis and necrosis, and prevented the mitochondrial permeability transition (MPT).
Kidney Int. 2012 Apr;81(7):662-73.
microglia
5 μM
6 h
Inhibited GSK3β phosphorylation, promoted Nrf2 nuclear accumulation, and reduced oxidative stress and inflammation
J Neuroinflammation. 2023 Feb 24;20(1):49.
TDZD-8 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
LPS-induced proteinuria and podocytopathy model
Intraperitoneal injection
5mg/kg
Single injection, lasting 24 hours
TDZD-8 therapy improved LPS-induced podocyte injury and proteinuria, suppressed podocytopathic mediators, but retained Bcl-xL in the glomerulus.
Kidney Int. 2015 Jun;87(6):1176-90.
Mice
DCLF-induced nephrotoxicity model
Intravenous injection
1 mg/kg, 5 mg/kg
Single dose, lasting 6 hours
TDZD-8 significantly improved kidney function, attenuated tubular necrosis and apoptosis, and inhibited the mitochondrial permeability transition (MPT) in DCLF-injured mice.
Kidney Int. 2012 Apr;81(7):662-73.
Mice
MRL/ lpr mice and (NZB × NZW)F1 mice
Intraperitoneal injection
5 mg/kg
Once daily for 8 weeks or 12 weeks
TDZD-8 treatment significantly attenuated severe proteinuria and renal inflammation in both mouse models, with a significant reduction in anti-dsDNA antibody production, renal immune complex deposition, and circulating proinflammatory cytokine levels.
Arthritis Rheumatol. 2015 Apr;67(4):1036-44
Mice
HgCl2-induced acute kidney injury model
Intraperitoneal injection
1 mg/kg and 0.5 mg/kg
Once on day 2 and day 3
TDZD-8 treatment accelerated the recovery of renal structure and function and increased cell proliferation.
Kidney Int. 2012 Nov;82(9):1000-9
Mice
RCDP models
Subcutaneous injection
5 mg/kg
Daily for 4 days
TDZD-8 restored Schwann cell differentiation and axonal sorting defects.
J Clin Invest. 2014 Jun;124(6):2560-70
Mice
Middle cerebral artery occlusion model
Intraperitoneal injection
5 mg/kg
Once daily for 3 days
Inhibited GSK3β phosphorylation, promoted Nrf2 nuclear accumulation, reduced oxidative stress and inflammation, and improved neurological function
J Neuroinflammation. 2023 Feb 24;20(1):49.
Mice
Prolonged learned helplessness model
Intraperitoneal injection
5mg/kg
Once daily for three days
Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3.
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