Background
IC50: A potent, selective and irreversible non-ATP-competitive GSK-3β suppressor with an IC50 of 60 nM.
Tideglusib is a GSK-3 inhibitor currently undergoing phase II clinical trials for Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of Tideglusib to animal models could down-regulates Tau hyper-phosphorylation, reduces brain amyloid plaque load, promotes learning and memory as well as prevents neuronal loss. [1]
In vitro: In vitro studies showed that after the unbound Tideglusib was removed from the reaction medium, the enzyme function could not be recovered. In addition, the dissociation rate constant of the reaction was as low as nearly zero. All above findings suggested that Tideglusib blocked GSK-3 irreversibly. Such irreversibility might be responsible for the non-competitive inhibition pattern with respect to ATP of Tideglusib and perhaps other structurally related compounds. [1]
In vivo: Based on double transgenic mice model co-expressing human mutant APP and tau, a study demonstrated that Tideglusib could suppress GSK-3, reduced amyloid and tau pathologies, blocked neuronal cell death and memory deficits in vivo. [2]
Clinical trial: A pilot, double-blind, placebo-controlled and randomized clinical trial was conducted to study the effect of Tideglusib in AD patients with an escalating dose. Thirty patients with mild to moderate AD were orally administered with Tideglusib in escalating doses of 400, 600, 800 and 1000 mg for periods of 4, 4, 6 and 6 weeks, respectively. This pilot study proved the safety and effectiveness of Tideglusib in AD patients. [3]
参考文献:
[1]Domínguez JM, Fuertes A, Orozco L, Monte-Millan MD, Delgado E and Medina M.? Evidence for irreversible inhibition of glycogen synthase kinase-3 by Tideglusib. J Biol Chem. 2012 Jan; 287(2): 893-904.
[2]Serenóa L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, Clarimón J, Lleó A, Gómez-Isla T.? A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009 Sep; 35(3): 359-67.
[3]del Ser, T.? Phase IIA clinical trial on Alzheimer’s Disease with NP-12, a GSK-3 inhibitor. Alzheimers and Dement. 2010; 6: S147.
Protocol
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Cell experiment [1]:
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Cell lines
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Spodoptera frugiperda Sf21 cells(expressing N-terminal His6-tagged human recombinant GSK-3β)
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Preparation method
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The solubility of this compound in DMSO >15 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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55μM for 1h at 25 °C .
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Applications
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Tideglusib blocked GSK-3β irreversibly in Sf21 cells transfected with human recombinant GSK-3β. It could prevent inflammation and neurodegeneration under excitotoxic conditions.
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Animal experiment [2]:
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Animal models
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Transgenic APPsw-tauvlw C57Bl6j/SJL/CBA mixed hybrid genetic mice( overexpressing human mutant APP and a triple human tau mutation (G272V, P301L and R406W at chromosome 17))
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Dosage form
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Reconstituted in 26% peg400 (Polyethylene Glycol 400), 15% Chremophor EL and water; 200 mg/kg daily for consecutive months; oral gavage
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Application
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Treatment with tideglusib resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1] Domínguez JM, Fuertes A, et al, Evidence for irreversible inhibition of glycogen synthase kinase-3 by Tideglusib. J Biol Chem. 2012 Jan; 287(2): 893-904.
[2] Luna-Medina R1, Cortes-Canteli M, et al, NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. J Neurosci. 2007 May 23;27(21):5766-76.
[3] Serenóa L, Coma M, et al, A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009 Sep; 35(3): 359-67.
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