Department of Vascular Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China.
Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China.
Mol Med Rep. 2021 Aug;24(2). doi: 10.3892/mmr.2021.12233. Epub 2021 Jun 24.
Lycopene has been reported to exert a protective effect on the brain against transient ischemia‑induced damage; however, whether it could regulate autophagic neuronal death remains elusive. The present study aimed to investigate the role of autophagy in the protective effects of lycopene against neuronal damage and its underlying mechanism. Oxygen‑glucose deprivation (OGD) was used to simulate neuronal ischemic injury in human SH‑SY5Y cells. Lactate dehydrogenase (LDH) release assay revealed that OGD induced SH‑SY5Y cell death. Western blotting demonstrated that OGD upregulated the expression levels of the autophagy marker proteins autophagy protein 5 (ATG5) and LC3II, but downregulated the autophagy substrate p62 in a time‑dependent manner. By contrast, OGD‑induced cell death was significantly inhibited by the autophagy inhibitors 3‑methyladenine or bafilomycin A1 or by knockdown of ATG5, indicating that OGD may induce autophagic death in SH‑SY5Y cells. Notably, lycopene was shown not only to prevent OGD‑induced SH‑SY5Y cell death, but was also able to effectively inhibit OGD‑induced upregulation of ATG5 and LC3II, and downregulation of p62 in a dose‑dependent manner. Mechanistically, it was suggested that lycopene inhibited OGD‑induced activation of the AMPK/mTOR pathway via attenuation of oxidative stress by maintaining the intracellular antioxidant glutathione (GSH). Furthermore, the inhibitory role of lycopene in GSH depletion was found to be associated with the prevention of OGD‑induced depletion of intracellular cysteine and downregulation of xCT. Collectively, the present study demonstrated that lycopene protected SH‑SY5Y cells against OGD‑induced autophagic death by inhibiting oxidative stress‑dependent activation of the AMPK/mTOR pathway.
番茄红素已被报道对脑缺血性损伤具有保护作用；然而，其是否能调节自噬性神经元死亡尚不清楚。本研究旨在探讨自噬在番茄红素对神经元损伤的保护作用及其潜在机制中的作用。氧葡萄糖剥夺（OGD）用于模拟人 SH-SY5Y 细胞的神经元缺血性损伤。乳酸脱氢酶（LDH）释放试验表明，OGD 诱导 SH-SY5Y 细胞死亡。Western blot 分析表明，OGD 呈时间依赖性地上调自噬标志物蛋白自噬蛋白 5（ATG5）和 LC3II 的表达水平，但下调自噬底物 p62。相反，自噬抑制剂 3-甲基腺嘌呤或巴弗洛霉素 A1 或 ATG5 敲低显著抑制 OGD 诱导的细胞死亡，表明 OGD 可能诱导 SH-SY5Y 细胞发生自噬性死亡。值得注意的是，番茄红素不仅能预防 OGD 诱导的 SH-SY5Y 细胞死亡，而且还能有效抑制 OGD 诱导的 ATG5 和 LC3II 上调，以及 p62 下调，呈剂量依赖性。在机制上，研究表明，番茄红素通过减轻氧化应激来抑制 OGD 诱导的 AMPK/mTOR 通路激活，从而维持细胞内抗氧化剂谷胱甘肽（GSH）。此外，发现番茄红素抑制 GSH 耗竭与预防 OGD 诱导的细胞内半胱氨酸耗竭和 xCT 下调有关。综上所述，本研究表明，番茄红素通过抑制氧化应激依赖性的 AMPK/mTOR 通路激活，保护 SH-SY5Y 细胞免受 OGD 诱导的自噬性死亡。
