CHIR-99021 is the most commonly used GSK-3β inhibitor and is considered the standard small-molecule Wnt agonist.CHIR-99021 is a potent inhibitor with high selectivity[[1].
CHIR-99021 led to a marked recovery in cell growth and viability suppressed by CDX2 overexpression. CHIR-99021 restored the protein levels of cyclin D1, c-myc, and β-catenin inhibited by overexpression of CDX2, as well as the cell growth and viability[2].
When the Human Tenon's fibroblasts(HTFs) were treated with TGF-β, a significant increase in the active form of GSK-3β was observed. A significant decrease in the active form of GSK-3β and molecules associated with fibrosis by TGF-β was noted in HTFs treated with CHIR-99021. CHIR-99021 treatment reduced the phosphorylated Smad2/Smad2 and phosphorylated Smad3/Smad3 ratios in HTFs and attenuated HTF migration[3].
The GSK-3 inhibitor CHIR 99021 trihydrochloride (0–10 mg/kg, ip) was injected 45-min prior to self-administration sessions in a counterbalanced design. After completion of the self-administration dose-effect curve, potential locomotor effects of the GSK-3 inhibitor were assessed. CHIR 99021 (10 mg/kg) dose-dependently increased alcohol reinforced responding with no effect on sucrose self-administration or locomotor activity. CHIR 99021 (10 mg/kg) significantly decreased pGSK-3β expression in all brain regions tested, reduced PICK1 and increased GluA2 total expression only in the NAcb.?Signaling through the GSK-3 / PICK1 / GluA2 molecular pathway drives the positive reinforcing effects of the drug, which are required for abuse liability[4].
CHIR-99021是最常用的GSK-3β抑制剂，被认为是标准的小分子Wnt激动剂。它是一种高选择性的强效抑制剂。
CHIR-99021可以显著促进细胞生长和存活，这些被CDX2过度表达所抑制的。CHIR-99021恢复了由于CDX2过度表达而受到抑制的cyclin D1、c-myc和β-catenin蛋白水平，同时也恢复了细胞生长和存活[2]。
当人类肌腱成纤维细胞（HTFs）接受TGF-β处理时，活性GSK-3β的显著增加。而在接受CHIR-99021处理的HTFs中，活性GSK-3β和与纤维化相关分子的活性形式明显降低。CHIR-99021治疗减少了HTFs中磷酸化Smad2/Smad2和磷酸化Smad3/Smad3比率，并减轻了HTF迁移[3]。
在一个平衡设计中，给小鼠注射GSK-3抑制剂CHIR 99021三盐酸盐（0-10毫克/千克，腹腔注射）45分钟后进行自我管理实验。完成自我管理剂量效应曲线后，评估了GSK-3抑制剂的潜在运动影响。CHIR 99021（10毫克/千克）依赖于剂量增加了对酒精的强化反应，在糖分自我管理或运动活动方面没有影响。 CHIR 99021（10毫克/千克）显着降低了所有测试大脑区域中pGSK-3β表达，并仅在NAcb中减少PICK1并增加GluA2总表达。通过GSK-3 / PICK1 / GluA2分子途径信号传导驱动药物的积极强化作用是滥用倾向所必需的[4]。
参考文献:
[1].Law SM, Zheng JJ. Premise and peril of Wnt signaling activation through GSK-3β inhibition. iScience. 2022 Mar 25;25(4):104159.
[2].Yu J, Liu D, et al. CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling via transactivation of GSK-3β and Axin2 expression. Cell Death Dis. 2019 Jan 10;10(1):26.?
[3].Lee SY, Chae MK, et al. The Effect of CHIR 99021, a Glycogen Synthase Kinase-3β Inhibitor, on Transforming Growth Factor β-Induced Tenon Fibrosis. Invest Ophthalmol Vis Sci. 2021 Dec 1;62(15):25.
[4].Faccidomo S, Holstein SE, et al. Pharmacological inhibition of glycogen synthase kinase 3 increases operant alcohol self-administration in a manner associated with altered pGSK-3β, protein interacting with C kinase and GluA2 protein expression in the reward pathway of male C57BL/6J mice. Behav Pharmacol. 2020 Feb;31(1):15-26.?
| Cell experiment [1]: | |
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Cell lines |
Human Tenon's fibroblasts |
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Preparation Method |
Human Tenon's fibroblasts?(HTFs) were pretreated with CHIR-99021, followed by treatment with 5 ng/mL of TGF-β for 30 minutes. For a quantitative evaluation of the level of gene transcription, quantitative real-time PCR was performed. |
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Reaction Conditions |
5, 10 μM CHIR-99021 for 48h. |
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Applications |
When HTFs were treated with 5 μM of CHIR 99021, with or without the addition of 5 ng/mL of TGF-b, there was a significant decrease in the production of the active form of GSK-3b, fibronectin, collagen Ia, and a-SMA.CHIR-99021 treatment attenuated the effects of TGF-b treatment, which had led to a significant increase in the phosphorylated Smad2/Smad2 and phosphorylated Smad3/Smad3 ratios. |
| Animal experiment [2]: | |
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Animal models |
C57BL/6J mice |
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Preparation Method |
The acquisition of operant alcohol and sucrose self-administration was established. Next, the selective GSK-3 inhibitor CHIR-99021 was injected 45 min prior to the start of the self-administration session. A maximum of 2 drug injections per week were conducted to ensure that responding returned to baseline after drug administration. |
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Dosage form |
CHIR-99021 0, 1, 3, or 10 mg/kg, i.p. injection |
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Applications |
CHIR-99021 (10 mg/kg) significantly increased the rate of alcohol-reinforced responding as compared to vehicle and that this effect emerged during and persisted throughout the second half of the 1-h session. The lower doses of CHIR 99021 did not alter alcohol reinforced response rate at any point throughout the session.? |
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参考文献: [1]. Lee SY, Chae MK, et al. The Effect of CHIR 99021, a Glycogen Synthase Kinase-3β Inhibitor, on Transforming Growth Factor β-Induced Tenon Fibrosis. Invest Ophthalmol Vis Sci. 2021 Dec 1;62(15):25.? [2]. Faccidomo S, Holstein SE, et al. Pharmacological inhibition of glycogen synthase kinase 3 increases operant alcohol self-administration in a manner associated with altered pGSK-3β, protein interacting with C kinase and GluA2 protein expression in the reward pathway of male C57BL/6J mice. Behav Pharmacol. 2020 Feb;31(1):15-26.? |
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