Zhang Yue, Hu Min, Tang Yue-Yu, Zhang Bei, Han Yin-Yin, Huang Zheng-Yu, Chen Chen, Li Gang
Department of Neurology, East Hospital, Tongji University School of Medicine, Tongji University School of Medicine, China.
Department of Neurology, East Hospital, Tongji University School of Medicine, Tongji University School of Medicine, China.
Biochem Biophys Res Commun. 2020 Feb 15. doi: 10.1016/j.bbrc.2020.02.061.
Long-term therapy with older antiepileptic drugs (AEDs), but not levetiracetam (LEV), may increase the risk of atherosclerosis (AS), suggesting that LEV may have a potential anti-AS effect. The synaptic vesicle 2A (SV2A) is known to the specific binding site of LEV. Numerous studies have documented that SV2A is a membrane protein specifically expressed in nervous system. Interestingly, our previous research showed that SV2A also existed in human CD8 T lymphocytes. Therefore, we hypothesized that LEV was associated with decreased risk of AS by regulating monocytes chemotaxis and adhesion. We showed that SV2A protein were detected in THP-1 human monocytic leukemia cells. LEV (300 μM) inhibited the chemotaxis and adhesion of THP-1 cells after transfection with plasmids expressing SV2A, but not SV2A which was a known functional mutation site of human SV2A. Furthermore, RT-PCR and western blot analysis demonstrated that LEV (300 μM) decreased the expression level of chemokine-related receptors (CX3CL1, CCR1, CCR2, and CCR5),and reduced levels of phosphorylated AKT (p-AKT) in THP-1 cells with SV2A expressing plasmids. Taken together, these findings indicated that LEV has an inhibitory effect on THP-1 monocyte adhesion and chemotaxis, suggesting that SV2A may serve as a novel therapeutic target to prevent AS.
使用 older 抗癫痫药物（AEDs）进行长期治疗，但左乙拉西坦（LEV）除外，可能会增加动脉粥样硬化（AS）的风险，这表明 LEV 可能具有潜在的抗 AS 作用。已知突触小泡 2A（SV2A）是 LEV 的特异性结合位点。大量研究表明，SV2A 是一种在神经系统中特异性表达的膜蛋白。有趣的是，我们之前的研究表明 SV2A 也存在于人类 CD8 T 淋巴细胞中。因此，我们推测 LEV 通过调节单核细胞趋化性和黏附与降低 AS 风险有关。我们发现 THP-1 人单核细胞白血病细胞中可检测到 SV2A 蛋白。在用表达 SV2A 的质粒转染后，LEV（300 μM）抑制了 THP-1 细胞的趋化性和黏附，但对已知的人类 SV2A 功能突变位点的 SV2A 则无此作用。此外，RT-PCR 和蛋白质印迹分析表明，LEV（300 μM）降低了表达 SV2A 质粒的 THP-1 细胞中趋化因子相关受体（CX3CL1、CCR1、CCR2 和 CCR5）的表达水平，并降低了磷酸化 AKT（p-AKT）的水平。综上所述，这些发现表明 LEV 对 THP-1 单核细胞黏附和趋化具有抑制作用，提示 SV2A 可能作为预防 AS 的新治疗靶点。
