Westmark Pamela R, Garrone Beatrice, Ombrato Rosella, Milanese Claudio, Di Giorgio Francesco Paolo, Westmark Cara J
Department of Neurology, University of Wisconsin, Madison, WI, United States.
Angelini Pharma S.p.A., Rome, Italy.
Front Mol Neurosci. 2021 Oct 7;14:751307. doi: 10.3389/fnmol.2021.751307. eCollection 2021.
Glycogen synthase kinase 3 (GSK3) is a proline-directed serine-threonine kinase that is associated with several neurological disorders, including Alzheimer's disease and fragile X syndrome (FXS). We tested the efficacy of a novel GSK3 inhibitor AFC03127, which was developed by Angelini Pharma, in comparison to the metabotropic glutamate receptor 5 inhibitor 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the GSK3 inhibitor SB216763 in and assays in mice, a mouse model useful for the study of FXS. The assay tested susceptibility to audiogenic-induced seizures (AGS) whereas the assays assessed biomarker expression and dendritic spine length and density in cultured primary neurons as a function of drug dose. MPEP and SB216763 attenuated AGS in mice, whereas AFC03127 did not. MPEP and AFC03127 significantly reduced dendritic expression of amyloid-beta protein precursor (APP). All drugs rescued spine length and the ratio of mature dendritic spines. Spine density was not statistically different between vehicle and GSK3 inhibitor-treated cells. The drugs were tested over a wide concentration range in the assays to determine dose responses. A bell-shaped dose response decrease in APP expression was observed in response to AFC03127, which was more effective than SB216763. These findings confirm previous studies demonstrating differential effects of various GSK3 inhibitors on AGS propensity in mice and confirm APP as a downstream biomarker that is responsive to GSK3 activity.
糖原合酶激酶3（GSK3）是一种脯氨酸定向的丝氨酸 - 苏氨酸激酶，与多种神经疾病相关，包括阿尔茨海默病和脆性X综合征（FXS）。我们测试了由安吉利尼制药公司研发的新型GSK3抑制剂AFC03127的疗效，并将其与代谢型谷氨酸受体5抑制剂2 - 甲基 - 6 - （苯乙炔基）吡啶盐酸盐（MPEP）以及GSK3抑制剂SB216763在FXS小鼠模型（一种对研究FXS有用的小鼠模型）的听源性惊厥（AGS）试验和培养的原代神经元中的生物标志物表达、树突棘长度和密度测定中进行比较。AGS试验测试对听源性惊厥的易感性，而测定则评估培养的原代神经元中生物标志物的表达、树突棘长度和密度作为药物剂量的函数。MPEP和SB216763减轻了FXS小鼠的AGS，而AFC03127则没有。MPEP和AFC03127显著降低了淀粉样β蛋白前体（APP）的树突表达。所有药物都挽救了树突棘长度和成熟树突棘的比例。在载体和GSK3抑制剂处理的细胞之间，树突棘密度没有统计学差异。在测定中，在很宽的浓度范围内测试了这些药物以确定剂量反应。观察到AFC03127引起APP表达呈钟形剂量反应下降，其比SB216763更有效。这些发现证实了先前的研究，即各种GSK3抑制剂对FXS小鼠的AGS倾向有不同影响，并证实APP是对GSK3活性有反应的下游生物标志物。
