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选择性阻断代谢型谷氨酸受体 mGluR5 可保护体外和体内缺血再灌注损伤模型中的小鼠肝脏。

Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury.

机构信息

Department of Internal Medicine and Therapeutics, Cellular and Molecular Pharmacology and Toxicology Unit, University of Pavia, 27100 Pavia, Italy.

Department of Physiology and Pharmacology, Sapienza University, 00185 Roma, Italy.

出版信息

Int J Mol Sci. 2018 Jan 23;19(2):314. doi: 10.3390/ijms19020314.

DOI:10.3390/ijms19020314
PMID:29360756
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5855547/
Abstract

2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion. We found that MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) deplete ATP in hepatocytes and acellular solutions, unlike fenobam. This finding suggests that mGluR5s may not be involved, contrary to previous reports. MPEP, as well as MTEP and fenobam, improved hypoxic hepatocyte viability, suggesting that protection against ischemic injury is independent of ATP depletion. Significantly, MPEP protected mouse livers in two different ex vivo models of ischemia reperfusion injury, suggesting its possible protective deployment in the treatment of hepatic inflammatory conditions.

摘要

2-甲基-6-(苯乙炔基)吡啶（MPEP）是代谢型谷氨酸受体（mGluR）5 的负变构调节剂，可保护肝细胞免受缺血性损伤。在星形胶质细胞和小胶质细胞中，MPEP 会消耗 ATP。这些发现似乎自相矛盾，因为 ATP 耗竭是缺血的基本应激源。本研究试图重建 MPEP 介导的 ATP 耗竭的机制以及 ATP 耗竭对缺血性损伤保护的影响。我们比较了 MPEP 和其他 mGluR5 负变构调节剂在大鼠肝细胞和无细胞溶液中测量时对 ATP 浓度的影响。我们还评估了 mGluR5 阻断对缺氧暴露的大鼠肝细胞活力的影响。此外，我们研究了 MPEP 处理对冷缺血和热缺血再灌注小鼠肝脏的影响。我们发现，MPEP 和 3-[(2-甲基-1,3-噻唑-4-基)乙炔基]吡啶（MTEP）可耗竭肝细胞和无细胞溶液中的 ATP，而芬诺巴则不然。这一发现表明，与之前的报告相反，mGluR5 可能不参与其中。MPEP 以及 MTEP 和芬诺巴均可改善缺氧性肝细胞活力，表明对缺血性损伤的保护与 ATP 耗竭无关。值得注意的是，MPEP 可保护两种不同的离体缺血再灌注损伤模型中的小鼠肝脏，这表明其在治疗肝脏炎症性疾病方面可能具有潜在的保护作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/21e494ae34b5/ijms-19-00314-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/129a21139691/ijms-19-00314-g008a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/2d911ba5a020/ijms-19-00314-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/21e494ae34b5/ijms-19-00314-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/136e7308c102/ijms-19-00314-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/ba0248c4ac2b/ijms-19-00314-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/129a21139691/ijms-19-00314-g008a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6374/5855547/2d911ba5a020/ijms-19-00314-g009.jpg
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