Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa)
Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa)
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DOI：
10.1016/j.neuropharm.2013.09.016
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发表时间：
2014-06
影响因子：
4.7
通讯作者：
Li-Ming Zhang;Nan Zhao;Wen-zhi Guo;Zeng Jin;Zhi-kun Qiu;Hong-xia Chen;Rui Xue;You-zhi Zhang;Ri-fang Yang;Yun‐feng Li
中科院分区：
文献类型：
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作者：
Li-Ming Zhang;Nan Zhao;Wen-zhi Guo;Zeng Jin;Zhi-kun Qiu;Hong-xia Chen;Rui Xue;You-zhi Zhang;Ri-fang Yang;Yun‐feng Li
已经证明，转运蛋白（18 kDa）（TSPO）在应激反应和应激相关疾病，如焦虑和抑郁症中起着重要作用，通过影响神经类固醇的产生，支持选择性TSPO配体作为抗抑郁或抗焦虑药物的潜在用途。N-乙基-N-（2-吡啶基甲基）-2-（3，4-氯苯基）-7-甲基咪唑并[1，2-a]吡啶-3-乙酰胺盐酸盐（YL-IPA 08）是我所合成的一种新型TSPO配体。正如所预期的，YL-IPA 08与培养的大鼠星形胶质细胞一起孵育增加了培养基中的双烯醇酮和孕酮浓度。此外，YL-IPA 08在一系列小鼠和大鼠行为模型中产生显著的抗抑郁样和抗焦虑样作用。此外，在悬尾实验中，YL-IPA 08的抗抑郁样行为被TSPO拮抗剂PK 11195完全阻断，在高架十字迷宫实验中，其抗焦虑作用被PK 11195阻断，但不被CBR拮抗剂阻断。此外，与CBR激动剂地西泮相比，YL-IPA 08没有肌松作用，并且不影响小鼠的运动协调性、记忆力或己巴比妥诱导的睡眠。总体而言，这些结果表明YL-IPA 08是更有效和选择性的TSPO配体，其对由TSPO介导的行为发挥抗抑郁样和抗焦虑样作用，但不会引起通常与常规苯二氮卓类药物相关的副作用。
It has been demonstrated that the translocator protein (18 kDa) (TSPO) plays an important role in stress-response and stress-related disorders, such as anxiety and depression, by affecting the production of neurosteroids, supporting the potential use of selective TSPO ligands as antidepressant or anxiolytic drugs. N-ethyl-N-(2-pyridinylmethyl)- 2-(3,4-ichlorophenyl)- 7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride (YL-IPA08), a novel TSPO ligand that has been synthesized at our institute, exerted a high affinity for TSPO in a crude mitochondrial fraction prepared from rat cerebellum but exhibited only a negligible affinity for the central benzodiazepine receptor. As expected, YL-IPA08 incubation with the cultured rat astrocyte cells increased the pregnenolone and progesterone concentration from the cultured medium. Moreover, YL-IPA08 produced significant antidepressant-like and anxiolytic-like effects in a series of mouse and rat behavior models. In addition, the antidepressant-like behavior of YL-IPA08 was totally blocked by the TSPO antagonist PK11195 in a tail suspension test, and the anxiolytic effect was blocked by PK11195 but not by a CBR antagonist in the elevated plus-maze test. Furthermore, compared with the CBR agonist diazepam, YL-IPA08 had no myorelaxant effects and did not affect the motor coordination, memory or hexobarbitone-induced sleep in mice. Overall, these results indicate that YL-IPA08 is a more potent and selective TSPO ligand, which exerts antidepressant-like and anxiolytic-like effects on behaviors that are mediated by TSPO but does not cause the side effects that are typically associated with conventional benzodiazepines.