Tideglusib is a potent, selective, and irreversible non-ATP competitive glycogen synthase kinase-3 (GSK-3) inhibitor. The IC50 values for GSK-3βWT and GSK-3βC199A are 5nM and 60nM, respectively [1]. GSK-3 is a serine/threonine kinase that is associated with glucose regulation, apoptosis, protein synthesis, cell signaling, cell transport, gene transcription, and cell proliferation [2]. Tideglusib can inhibit inflammation and neurodegenerative diseases and can be used to treat Alzheimer's disease [3-4].
In vitro, Tideglusib (2.5μM; 24h) completely eliminated the expression of TNF-α and COX-2 in glutamate-induced astrocyte and microglial cell cultures, and significantly reduced the number of laminin-V positive cells, exerting anti-inflammatory and neuroprotective effects on cortical neurons [5]. Different concentrations of Tideglusib (5-120μM; 48h) dose-dependently reduced the cell viability of human neuroblastoma (IMR32) cells [6].
In vivo, Tideglusib (2ng/2.5μl PBS; stereotactic injection) treatment significantly improved brain injury in kainic acid (KA) induced focal excitotoxicity model rats and reduced TNF-α positive staining in astrocytes and microglia [5]. Tideglusib (200mg/kg/day; 3 months) oral treatment reduced tau protein phosphorylation levels in APP/tau double transgenic mice, decreased amyloid protein deposition and plaque-related astrocyte proliferation, and protected the entorhinal cortex and prevented hippocampal CA1 zone neuron death [7].
References:
[1] Domínguez JM, Fuertes A, Orozco L, et al. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J Biol Chem. 2012;287(2):893-904.
[2] Pandey M K, DeGrado T R. Glycogen synthase kinase-3 (GSK-3)-targeted therapy and imaging[J]. Theranostics, 2016, 6(4): 571.
[3] Serenóa L, Coma M, Rodríguez 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.
[4] Lovestone S, Boada M, Dubois B, et al. A phase II trial of tideglusib in Alzheimer's disease[J]. Journal of Alzheimer’s Disease, 2015, 45(1): 75-88.
[5] Luna-Medina R, Cortes-Canteli M, Sanchez-Galiano S, et al. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders[J]. Journal of Neuroscience, 2007, 27(21): 5766-5776.
[6] Mathuram, Theodore Lemuel et al. “Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G0/G1 accumulation and ROS generation.” Environmental toxicology and pharmacology vol. 46 (2016): 194-205.
[7] Serenó, L et al. “A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo.” Neurobiology of disease vol. 35,3 (2009): 359-67.
Tideglusib是一种强效、选择性且不可逆的非ATP竞争性糖原合成酶激酶-3（GSK-3）抑制剂，对GSK-3βWT和GSK-3βC199A的IC50分别为5nM和60nM [1]。GSK-3是一种丝氨酸/苏氨酸激酶，与葡萄糖调节、细胞凋亡、蛋白质合成、细胞信号传导、细胞运输、基因转录和细胞增殖等生物学过程相关联 [2]。Tideglusib能够抑制炎症和神经退行性病变，可用于治疗阿尔茨海默病 [3-4]。
在体外，Tideglusib（2.5μM; 24h）完全消除了谷氨酸诱导的星形胶质细胞和小胶质细胞培养物中TNF-α和COX-2的表达，并显著减少了膜联蛋白-V阳性细胞的数量，对皮质神经元有抗炎和神经保护作用 [5]。不同浓度的Tideglusib（5-120μM; 48h）剂量依赖性地降低了人类神经母细胞瘤(IMR32)的细胞活力 [6]。
在体内，Tideglusib（2ng/2.5μl PBS; stereotactic injection）治疗显著改善了kainic acid（KA）诱导的局灶性兴奋性毒性模型大鼠的脑损伤，并降低了星形胶质细胞和小胶质细胞中的TNF-α阳性染色 [5]。Tideglusib（200mg/kg/day; 3 months）口服治疗降低了APP/tau双转基因小鼠中tau蛋白磷酸化水平，减少淀粉样蛋白沉积和斑块相关的星形胶质细胞增殖，同时保护内嗅皮层和防止海马CA1区神经元死亡 [7]。