Lee Hyun-Su, Jeong Gil-Saeng
College of Pharmacy, Keimyung University, Daegu 42601, Korea.
Molecules. 2021 Apr 22;26(9):2442. doi: 10.3390/molecules26092442.
Methamphetamine (METH) is a synthetic psychostimulant drug that has detrimental effects on the health of its users. Although it has been investigated as a cause of neurodegenerative disease due to its neurotoxicity, whether small molecules derived from natural products attenuate these side effects remains elusive. 6,7,4'-trihydroxyflavanone (THF) is a flavanone family that possesses various pharmacological activities, including anti-rheumatic, anti-ischemic, anti-inflammatory, anti-osteoclastogenic, and protective effects against METH-induced deactivation of T cells. However, little is known about whether THF protects neuronal cells from METH-induced neurotoxicity. Here, we investigated the protective effects of THF on neurotoxicity induced by METH exposure by enhancing the Nrf2/HO-1 and PI3K/Akt/mTOR signaling pathways in SH-SY5y cells. Treatment with THF did not lead to cytotoxicity, but attenuated METH-induced neurotoxicity by modulating the expression of apoptosis-related proteins, METH-induced oxidative stress, and PI3K/Akt/mTOR phosphorylation in METH-exposed SH-SY5y cells. Moreover, we found THF induced Nrf2 nuclear translocation and HO-1 expression. An inhibitor assay confirmed that the induction of HO-1 by THF attenuates METH-induced neurotoxicity. Therefore, we suggest that THF preserves neuronal cells from METH-induced neurotoxicity by upregulating HO-1 expression through the Nrf2 and PI3K/Akt/mTOR signaling pathways. Thus, THF has therapeutic potential for use in the treatment of METH-addicts suffering from neurodegenerative diseases.
甲基苯丙胺（METH）是一种合成的精神刺激药物，对使用者的健康有有害影响。尽管由于其神经毒性，它已被研究作为神经退行性疾病的一个病因，但源自天然产物的小分子是否能减轻这些副作用仍不清楚。6,7,4'-三羟基黄酮（THF）是一种黄酮类化合物，具有多种药理活性，包括抗风湿、抗缺血、抗炎、抗破骨细胞生成以及对METH诱导的T细胞失活的保护作用。然而，关于THF是否能保护神经元细胞免受METH诱导的神经毒性知之甚少。在此，我们通过增强SH-SY5y细胞中的Nrf2/HO-1和PI3K/Akt/mTOR信号通路，研究了THF对METH暴露诱导的神经毒性的保护作用。THF处理不会导致细胞毒性，但通过调节METH暴露的SH-SY5y细胞中凋亡相关蛋白的表达、METH诱导的氧化应激以及PI3K/Akt/mTOR磷酸化，减轻了METH诱导的神经毒性。此外，我们发现THF诱导Nrf2核转位和HO-1表达。抑制剂实验证实，THF诱导的HO-1可减轻METH诱导的神经毒性。因此，我们认为THF通过Nrf2和PI3K/Akt/mTOR信号通路上调HO-1表达，从而保护神经元细胞免受METH诱导的神经毒性。因此，THF在治疗患有神经退行性疾病的METH成瘾者方面具有治疗潜力。
