背景:帕金森病(PD)是一种不可逆转的疾病,进行性障碍,深刻影响运动和非运动功能,从而显著降低个人的生活质量。二氢西诺林(DHS),一种来自软珊瑚的天然生物活性分子,表现出低细胞毒性和抗炎特性。然而,目前尚不清楚DHS对神经毒素和PD的治疗作用.
目的:这项研究调查了DHS是否可以减轻6-羟基多巴胺(6-OHDA)诱导的神经毒性,并探讨了神经保护性PI3K下游信号通路的作用,包括AKT,ERK,JNK,BCL2和NFκB,在DHS介导的神经保护中。
方法:我们处理了人神经母细胞瘤细胞系,SH-SY5Y,用神经毒素6-OHDA建立PD的细胞模型。同时,我们通过细胞活力评估了DHS的抗凋亡和神经保护特性,凋亡,和免疫染色测定。此外,我们利用PI3K抑制剂LY294002来验证DHS的治疗靶点.
结果:根据DHS的理化性质,可以推断,它具有良好的口服生物利用度和通过血脑屏障(BBB)的渗透性。已证明DHS上调磷酸化的AKT和ERK,同时下调磷酸化的JNK。因此,这增强了BCL2的表达,BCL2通过抑制caspase活性和防止细胞凋亡而对神经元细胞发挥保护作用。抑制PI3K显著降低DHS在6-OHDA诱导的神经毒性中的相对保护活性,提示DHS的神经保护作用是通过激活PI3K信号介导的。
结论:通过研究6-OHDA诱导的神经毒性的机制,我们提供了有关DHS在神经保护方面的治疗潜力的证据.对DHS及其作用机制的进一步研究有望开发新的PD治疗策略。
BACKGROUND: Parkinson\'s disease (PD) is an irreversible, progressive disorder that profoundly impacts both motor and non-motor functions, thereby significantly diminishing the individual\'s quality of life. Dihydrosinularin (DHS), a natural bioactive molecule derived from soft corals, exhibits low cytotoxicity and anti-inflammatory properties. However, the therapeutic effects of DHS on neurotoxins and PD are currently unknown.
OBJECTIVE: This study investigated whether DHS could mitigate 6-hydroxydopamine (6- OHDA)-induced neurotoxicity and explored the role of neuroprotective PI3K downstream signaling pathways, including that of AKT, ERK, JNK, BCL2, and NFκB, in DHS- mediated neuroprotection.
METHODS: We treated the human neuroblastoma cell line, SH-SY5Y, with the neurotoxin 6-OHDA to establish a cellular model of PD. Meanwhile, we assessed the anti-apoptotic and neuroprotective properties of DHS through cell viability, apoptosis, and immunostaining assays. Furthermore, we utilized the PI3K inhibitor LY294002 to validate the therapeutic target of DHS.
RESULTS: Based on the physicochemical properties of DHS, it can be inferred that it has promising oral bioavailability and permeability across the blood-brain barrier (BBB). It was demonstrated that DHS upregulates phosphorylated AKT and ERK while downregulating phosphorylated JNK. Consequently, this enhances the expression of BCL2, which exerts a protective effect on neuronal cells by inhibiting caspase activity and preventing cell apoptosis. The inhibition of PI3K significantly reduced the relative protective activity of DHS in 6-OHDA-induced neurotoxicity, suggesting that the neuroprotective effects of DHS are mediated through the activation of PI3K signaling.
CONCLUSIONS: By investigating the mechanisms involved in 6-OHDA-induced neurotoxicity, we provided evidence concerning the therapeutic potential of DHS in neuroprotection. Further research into DHS and its mechanisms of action holds promise for developing novel therapeutic strategies for PD.