IC50型
星形胶质细胞
效力
化学
药理学
促炎细胞因子
体外
生物化学
生物
炎症
免疫学
内分泌学
中枢神经系统
作者
Katarina Mihajlović,Marija Adžić,Milorad Dragić,Mirko Scortichini,Kenneth A. Jacobson,Nadežda Nedeljković
标识
DOI:10.1016/j.ejphar.2023.175943
摘要
Three novel cytosine-derived α,β-methylene diphosphonates designated MRS4598, MRS4552, and MRS4602 were tested in the range of 1 × 10-9 to 1 × 10-3 M for their efficacy and potency in inhibiting membrane-bound ecto-5'-nucleotidase/CD73 activity in primary astrocytes in vitro. The compounds were also tested for their ability to attenuate the reactive astrocyte phenotype induced by proinflammatory cytokines. The main findings are as follows: A) The tested compounds induced concentration-dependent inhibition of CD73 activity, with maximal inhibition achieved at ∼1 × 10-3M; B) All compounds showed high inhibitory potency, as reflected by IC50 values in the submicromolar range; C) All compounds showed high binding capacity, as reflected by Ki values in the low nanomolar range; D) Among the tested compounds, MRS4598 showed the highest inhibitory efficacy and potency, as reflected by IC50 and Ki values of 0.11 μM and 18.2 nM; E) Neither compound affected astrocyte proliferation and cell metabolic activity at concentrations near to IC50; E) MRS4598 was able to inhibit CD73 activity in reactive astrocytes stimulated with TNF-α and to induce concentration-dependent inhibition of CD73 in reactive astrocytes stimulated with IL-1β, with an order of magnitude higher IC50 value; F) MRS4598 was the only compound tested that was able to induce shedding of the CD73 from astrocyte membranes and to enhance astrocyte migration in the scratch wound migration assay, albeit at concentration well above its IC50 value. Given the role of CD73 in neurodegenerative diseases, MRS4598, MRS4552, and MRS4602 are promising pharmacological tools for the treatment of neurodegeneration and neuroinflammation.
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