Institute of Mental Health, Jining Medical University, Jining, Shandong, 272067, China.
Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, Xiamen, 361000, China.
Mol Biol Rep. 2024 May 24;51(1):669. doi: 10.1007/s11033-024-09587-2.
The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear.
An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2 h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24 h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK).
OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells.
This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.
黑质致密部（SNpc）中多巴胺能（DA）神经元的丧失是帕金森病（PD）的主要病理标志。已经报道脑肠肽（OXB）可促进 DA 神经元的生长。然而，OXB 在 DA 神经元变性中的作用仍不完全清楚。
通过在小鼠中给予 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）构建体内 PD 模型。通过 pole 试验检测小鼠的运动功能，通过免疫荧光（IF）检测 DA 神经元的数量。通过用 1-甲基-4-苯基吡啶鎓（MPP+）处理 SH-SY5Y 细胞建立 PD 细胞模型。在 MPP+处理后 2 h 将 OXB 添加到培养基中。在 MPP+挑战后 24 h 通过显微镜分析研究 OXB 在 PD 细胞模型中的功能。对 PD 细胞模型进行 RNA-Seq 分析以探讨可能的机制。使用 Western blot 检测细胞外信号调节激酶（ERK）的磷酸化水平。
OXB 显著降低了 MPTP 引起的 DA 神经元死亡，减轻了 MPP+诱导的 SH-SY5Y 细胞神经毒性，并显著增强了 PD 小鼠的体重和运动能力。此外，RNA-Seq 分析表明丝裂原活化蛋白激酶（MAPK）途径参与了 PD 的病理学。此外，MPP+导致 ERK（p-ERK）的磷酸化水平增加，而 OXB 处理可显著降低 MPP+处理的 SH-SY5Y 细胞中 p-ERK 的水平。
本研究表明，OXB 在 PD 模型中发挥神经保护作用，与减少 ERK 磷酸化有关。这表明 OXB 可能具有治疗 PD 的潜力。
