High Glucose Enhances Bupivacaine-induced Neurotoxicity via MCU-mediated Oxidative Stress in SH-SY5Y Cells
High Glucose Enhances Bupivacaine-induced Neurotoxicity via MCU-mediated Oxidative Stress in SH-SY5Y Cells
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高葡萄糖通过 MCU 介导的 SH-SY5Y 细胞氧化应激增强布比卡因诱导的神经毒性
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通讯作者：
Shi-Yuan Xu
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作者：
Zhong-Jie Liu;Wei Zhao;Hong-Yi Lei;Hua-Li Xu;Lu-Ying Lai;Rui Xu;Shi-Yuan Xu
布比卡因是一种典型的局部麻醉药，通过活性氧调节细胞凋亡诱导神经毒性。高糖可通过调节氧化应激增强布比卡因的神经毒性，但其机制尚不清楚。线粒体钙单向转运体（MCU）是调节线粒体钙内流的关键通道，通过破坏mCa 2+稳态与氧化应激密切相关。MCU是否参与高糖致敏布比卡因诱导的神经毒性仍不清楚。本研究采用人神经母细胞瘤（SH-SY 5 Y）细胞，在高糖和/或布比卡因的共同作用下，发现高糖可增强布比卡因诱导的MCU表达升高、mCa 2+蓄积和氧化损伤。结果表明，Ru 360能降低高糖和布比卡因诱导的细胞内游离钙（mCa 2+）积累、氧化应激和细胞凋亡。在SH-SY 5 Y细胞中用特异性小干扰RNA（siRNA）敲低MCU，发现其也能抑制高糖和布比卡因诱导的mCa 2+蓄积、氧化应激和细胞凋亡。我们认为，下调MCU通道的表达或抑制MCU通道的活性可能有助于恢复线粒体功能，对抗高糖和布比卡因诱导的神经毒性。总之，我们的研究证明了MCU在高糖介导的布比卡因诱导的神经毒性增强中的关键作用，表明该通道可能用作治疗糖尿病患者布比卡因诱导的神经毒性的靶点。
Bupivacaine, a typical local anesthetic, induces neurotoxicity via reactive oxygen species regulation of apoptosis. High glucose could enhance bupivavaine-induced neurotoxicity though regulating oxidative stress, but the mechanism of it is not clear. Mitochondrial calcium uniporter (MCU), a key channel for regulating mitochondrial Ca2+ (mCa2+) influx, is closely related to oxidative stress via disruption of mCa2+ homeostasis. Whether MCU is involved in high glucose sensitized bupivacaine-induced neurotoxicity remains unknown. In this study, human neuroblastoma (SH-SY5Y) cells were cultured with high glucose and/or bupivaciane, and the data showed that high glucose enhanced bupivacaine-induced MCU expression elevation, mCa2+ accumulation and oxidative damage. Next, Ru360, an inhibitor of MCU, was employed to pretreated SH-SY5Y cells, and the results showed that it could decrease high glucose and bupivacaine-induced mCa2+ accumulation, oxidative stress and apoptosis. Further, knock-down of MCU with a specific small interfering RNA (siRNA) in SH-SY5Y cells, we found that it also could inhibit high glucose and bupivacaine-induced mCa2+ accumulation, oxidative stress and apoptosis. We propose that down-regulation expression or activity inhibition of MCU channel might be useful for restoring the mitochondrial function and combating high glucose and bupivacaine-induced neurotoxicity. In conclusion, our study demonstrated the crucial role of MCU in high glucose-mediated enhancement of bupivacaine-induced neurotoxicity, suggesting the possible use of this channel as a target for curing bupivacaine-induced neurotoxicity in diabetic patients.