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体内和体外癫痫和炎症模型中小鼠小胶质细胞对犬尿氨酸的敏感性:犬尿酸和合成类似物 SZR104 抑制小胶质细胞激活。

Sensitivity of Rodent Microglia to Kynurenines in Models of Epilepsy and Inflammation In Vivo and In Vitro: Microglia Activation is Inhibited by Kynurenic Acid and the Synthetic Analogue SZR104.

机构信息

Department of Cell Biology and Molecular Medicine, University of Szeged, 6720 Szeged, Hungary.

Department of Laboratory Medicine, University of Szeged, 6720 Szeged, Hungary.

出版信息

Int J Mol Sci. 2020 Dec 7;21(23):9333. doi: 10.3390/ijms21239333.

Abstract

Kynurenic acid is an endogenous modulator of ionotropic glutamate receptors and a suppressor of the immune system. Since glutamate and microglia are important in the pathogenesis of epilepsy, we investigated the possible action of the synthetic kynurenic acid analogue, SZR104, in epileptic mice and the action of kynurenic acid and SZR104 on the phagocytotic activity of cultured microglia cells. Pilocarpine epilepsy was used to test the effects of SZR104 on morphological microglia transformation, as evaluated through ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Microglia-enriched rat secondary cultures were used to investigate phagocytosis of fluorescent microbeads and Iba1 protein synthesis in control and lipopolysaccharide-challenged cultures. SZR104 inhibited microglia transformation following status epilepticus. Kynurenic acid and SZR104 inhibited lipopolysaccharide-stimulated phagocytotic activity of microglia cells. Although kynurenic acid and its analogues proved to be glutamate receptor antagonists, their immunosuppressive action was dominant in epilepsy. The inhibition of phagocytosis in vitro raised the possibility of the inhibition of genes encoding inflammatory cytokines in microglial cells.

摘要

犬尿酸是一种内源性离子型谷氨酸受体调节剂和免疫系统抑制剂。由于谷氨酸和小胶质细胞在癫痫发病机制中很重要,我们研究了合成犬尿酸类似物 SZR104 在癫痫小鼠中的可能作用,以及犬尿酸和 SZR104 对培养的小胶质细胞吞噬活性的作用。匹罗卡品癫痫用于测试 SZR104 对形态学小胶质细胞转化的影响,通过离子钙结合衔接分子 1(Iba1)免疫组织化学进行评估。使用富含小胶质细胞的大鼠二级培养物来研究荧光微球的吞噬作用和对照及脂多糖刺激培养物中 Iba1 蛋白的合成。SZR104 抑制癫痫持续状态后的小胶质细胞转化。犬尿酸和 SZR104 抑制脂多糖刺激的小胶质细胞吞噬活性。尽管犬尿酸及其类似物被证明是谷氨酸受体拮抗剂,但它们在癫痫中的免疫抑制作用占主导地位。体外吞噬作用的抑制提出了抑制小胶质细胞中编码炎症细胞因子的基因的可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2af9/7731372/8c04a4c4f773/ijms-21-09333-g001.jpg

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