Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
J Ethnopharmacol. 2020 May 10;253:112636. doi: 10.1016/j.jep.2020.112636. Epub 2020 Jan 28.
Lipid homoeostasis is important for neurodevelopment, cell signaling and neurotransmission. Alteration of lipid metabolism has been demonstrated in many neurological disorders and neurodegenerative diseases. Geissoschizine methyl ether (GM) is an active alkaloid ingredient in the traditional Chinese medicine Uncaria hook. It has been shown that GM has strong potency in neuroprotective activity and GM reduces the production of reactive oxygen species by regulating glucose metabolism, which protects neurons against oxidative stress-induced cell death. However, it is unknown whether GM could regulate neuronal lipid metabolism during oxidative challenge.
The current study aimed to explore whether GM regulates lipid metabolism in oxidative damaged neurons and to determine the underlying mechanism involved in this neuro-protection.
Using a glutamate-induced oxidative toxicity model in mouse hippocampal neuronal cell line (HT-22 cells), we investigated the effect of GM on glutamate-induced lipid peroxidation, lipotoxicity and mitochondrial dysfunction. In order to clarify the mechanism underlying the neuroprotection by GM, lipid metabolomics was performed to investigate whether GM prevent oxidative stress-induced lipid metabolism disruption. Furthermore, the expression of lipid metabolism-related genes was measured.
The results show the protective effect of GM against oxidative stress through blocking glutamate-induced lipid peroxidation and lipotoxicity. Overall, lipidomics analysis revealed that glutamate treatment resulted in different extents of changes in a wide range of lipid classes such as fatty acids (FA), triacylglycerol (TG), sphingomyelin (SM), cardiolipin (CL), lysophosphatidylcholines (LPC). However, GM treatment can significantly reverse glutamate-induced lipids disorder to the homeostasis level. GM prevented the disruption of lipid metabolism by regulating the expression of lipid homeostasis related genes, which contributes to preserve mitochondrial function under oxidative damage.
These findings clearly demonstrated a novel protective mechanism of GM against glutamate-induced oxidative toxicity in neurons via regulating lipid metabolism. GM may provide an effective approach for the prevention and treatment of oxidative damaged neurons.
脂质动态平衡对神经发育、细胞信号转导和神经传递很重要。许多神经紊乱和神经退行性疾病都表现出脂质代谢的改变。钩藤中的活性生物碱成分吉非替尼甲醚（GM）已被证明具有很强的神经保护活性，GM 通过调节葡萄糖代谢来减少活性氧的产生，从而保护神经元免受氧化应激诱导的细胞死亡。然而，目前尚不清楚 GM 是否可以在氧化应激下调节神经元的脂质代谢。
本研究旨在探讨 GM 是否调节氧化应激损伤神经元中的脂质代谢，并确定这种神经保护作用的潜在机制。
采用谷氨酸诱导的小鼠海马神经元细胞系（HT-22 细胞）氧化毒性模型，研究 GM 对谷氨酸诱导的脂质过氧化、脂毒性和线粒体功能障碍的影响。为了阐明 GM 神经保护作用的机制，我们进行了脂质组学研究，以探讨 GM 是否能防止氧化应激引起的脂质代谢紊乱。此外，还测量了与脂质代谢相关的基因的表达。
结果表明，GM 通过阻断谷氨酸诱导的脂质过氧化和脂毒性，对氧化应激具有保护作用。总的来说，脂质组学分析显示，谷氨酸处理导致了广泛的脂质类别的不同程度的变化，如脂肪酸（FA）、三酰甘油（TG）、神经鞘磷脂（SM）、心磷脂（CL）、溶血磷脂酰胆碱（LPC）。然而，GM 处理可以显著逆转谷氨酸诱导的脂质紊乱，使其恢复到平衡状态。GM 通过调节脂质平衡相关基因的表达来防止脂质代谢的破坏，这有助于在氧化损伤下维持线粒体功能。
这些发现清楚地表明，GM 通过调节脂质代谢，为神经元中谷氨酸诱导的氧化毒性提供了一种新的保护机制。GM 可能为氧化损伤神经元的预防和治疗提供一种有效方法。
