GET73 modulates lipopolysaccharide- and ethanol-induced increase in cytokine/chemokine levels in primary cultures of microglia of rat cerebral cortex.

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pharmacological Reports Pub Date : 2024-10-01 Epub Date: 2024-08-01 DOI:10.1007/s43440-024-00632-2

Maria C Tomasini, Antonella Loche, Roberto Cacciaglia, Luca Ferraro, Sarah Beggiato

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引用次数: 0

Abstract

Background: - Alcohol-induced pro-inflammatory activation might influence cellular and synaptic pathology, thus contributing to the behavioral phenotypes associated with alcohol use disorders. In the present study, the possible anti-inflammatory properties of N-[(4-trifluoromethyl)-benzyl]4-methoxybutyramide (GET73), a promising therapeutic agent for alcohol use disorder treatment, were evaluated in primary cultures of rat cortical microglia.

Methods: - Primary cultures of cerebral cortex microglial cells were treated with 100 ng/ml lipopolysaccharide (LPS; 8 h, 37 °C) or 75 mM ethanol (EtOH; 4 days, 37 °C) alone or in the presence of GET73 (1-30 µM). At the end of the incubation period, multiparametric quantification of cytokines/chemokines was performed by using the xMAP technology and Luminex platform. Furthermore, cultured microglial cell viability following the treatment with EtOH and GET73, alone or in combination, has been measured by a colorimetric assay (i.e. MTT assay).

Results: - GET73 (10 and 30 µM) partially or fully prevented the LPS-induced increase of IL-6, IL-1β, RANTES/CCL5 protein and MCP-1/CCL2 levels. On the contrary, GET73 failed to attenuate the TNF-α level increase induced by LPS. Furthermore, GET73 treatment (10-30 µM) significantly attenuated or prevented the EtOH-induced increase of TNF-α, IL-6, IL-1β and MCP-1/CCL2 levels. Finally, at all the concentrations tested (1-30 µM), the GET73 treatment did not alter the EtOH-induced reduction of microglial cell viability.

Conclusions: - The current results provide the first in vitro evidence of GET73 protective properties against EtOH-induced neuroinflammation. These data add more information on the complex and multifactorial profile of action of the compound, further supporting the significance of developing GET73 as a therapeutic tool for the treatment of individuals with alcohol use disorders.

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GET73 可调节脂多糖和乙醇诱导的大鼠大脑皮层小胶质细胞原代培养物中细胞因子/趋化因子水平的升高。

背景：- 酒精诱导的促炎激活可能会影响细胞和突触病理学，从而导致与酒精使用障碍相关的行为表型。本研究在大鼠皮质小胶质细胞的原代培养物中评估了 N-[(4-三氟甲基)-苄基]4-甲氧基丁酰胺（GET73）可能具有的抗炎特性。方法：- 用 100 纳克/毫升脂多糖（LPS；8 小时，37 °C）或 75 毫摩尔乙醇（EtOH；4 天，37 °C）单独或在 GET73（1-30 µM）存在下处理大脑皮层小胶质细胞原代培养物。培养期结束后，使用 xMAP 技术和 Luminex 平台对细胞因子/凝血因子进行多参数定量。此外，用比色法（即 MTT 法）测量了单独或联合使用 EtOH 和 GET73 处理后培养的小胶质细胞的存活率：- 结果：GET73（10 和 30 µM）部分或完全阻止了 LPS 诱导的 IL-6、IL-1β、RANTES/CCL5 蛋白和 MCP-1/CCL2 水平的增加。相反，GET73 未能抑制 LPS 诱导的 TNF-α 水平的升高。此外，GET73 处理剂（10-30 µM）可明显减轻或阻止 EtOH 诱导的 TNF-α、IL-6、IL-1β 和 MCP-1/CCL2 水平的增加。最后，在所有测试浓度（1-30 µM）下，GET73 处理都不会改变 EtOH 诱导的小胶质细胞活力下降：- 目前的研究结果首次在体外证明了 GET73 对 EtOH 引起的神经炎症具有保护作用。这些数据为该化合物复杂而多因素的作用特征提供了更多信息，进一步支持了将 GET73 开发为治疗酒精使用障碍患者的治疗工具的意义。

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来源期刊

Pharmacological Reports 医学-药学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.