Wen Zhi-Hong, Chiu Ya-Jen, Yang San-Nan, Huang Tzu-Yi, Feng Chien-Wei, Chen Nan-Fu, Sung Chun-Sung, Chen Wu-Fu
National Sun Yat-sen University Department of Marine Biotechnology and Resources Kaohsiung City Taiwan.
Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833301, Taiwan.
Curr Med Chem. 2024 Sep 3;32(8):1606-20. doi: 10.2174/0109298673323198240823070219.
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.
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.
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.
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.
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.
帕金森病（PD）是一种不可逆的进行性疾病，对运动和非运动功能均有深远影响，从而显著降低个体的生活质量。二氢松萝酸（DHS）是一种源自软珊瑚的天然生物活性分子，具有低细胞毒性和抗炎特性。然而，DHS对神经毒素和PD的治疗作用目前尚不清楚。
本研究调查DHS是否能减轻6-羟基多巴胺（6-OHDA）诱导的神经毒性，并探讨神经保护PI3K下游信号通路，包括AKT、ERK、JNK、BCL2和NFκB在DHS介导的神经保护中的作用。
我们用神经毒素6-OHDA处理人神经母细胞瘤细胞系SH-SY5Y，以建立PD细胞模型。同时，我们通过细胞活力、凋亡和免疫染色试验评估DHS的抗凋亡和神经保护特性。此外，我们使用PI3K抑制剂LY294002来验证DHS的治疗靶点。
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穿过血脑屏障（BBB）的通透性。结果表明，DHS上调磷酸化AKT和ERK，同时下调磷酸化JNK。因此，这增强了BCL2的表达，BCL2通过抑制半胱天冬酶活性和防止细胞凋亡对神经元细胞发挥保护作用。PI3K的抑制显著降低了DHS在6-OHDA诱导的神经毒性中的相对保护活性，表明DHS的神经保护作用是通过PI3K信号的激活介导的。
通过研究6-OHDA诱导神经毒性的相关机制，我们提供了有关DHS在神经保护方面治疗潜力的证据。对DHS及其作用机制的进一步研究有望为PD开发新的治疗策略。
