Li Qi, Han Xiaoxuan, Dong Mengmeng, Bai Lipeng, Zhang Wei, Liu Wei, Wang Fei, Zhu Xiaodong
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road 154#, Tianjin, 300052, China.
Inflammation. 2025 Feb 26. doi: 10.1007/s10753-025-02267-8.
Interleukin-17A (IL-17A) has been implicated in the progression of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the effect of the FDA-approved Secukinumab (SEC), an IL-17A inhibitor, on PD remains unclear. This study aimed to investigate the neuroprotective effect of SEC and its potential mechanisms in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Male C57BL/6 J mice were mainly assigned to three groups: Sham, MPTP, and MPTP + SEC. Motor coordination was assessed using the climbing rod and rotarod tests. Dopaminergic neurons (TH +) and glial cells (Iba-1 + , GFAP +) in the substantia nigra were evaluated using immunohistochemistry and immunofluorescence. Flow cytometry was used to analyze immune cell populations in the brain and spleen. Inflammatory cytokines and chemokines were quantified using RT-PCR. SEC treatment significantly alleviated the loss of dopaminergic neurons and improved motor coordination in MPTP mice. It also reduced the infiltration of peripheral immune cells, including CD4 + T cells, NK cells, and monocyte-macrophages into the brain. SEC attenuated glial activation (Iba-1 + , GFAP +) and decreased the expression of pro-inflammatory cytokines and chemokines (CCL2, CXCL9), which recruit immune cells into the brain. These results suggest that Secukinumab protects dopaminergic neurons and attenuates neuroinflammation in MPTP-induced model. SEC treatment in PD might be an effective therapeutic approach for clinical application in the future. HIGHLIGHTS: • Secukinumab reduces the loss of dopaminergic neurons and axons in MPTP mice. • Secukinumab inhibits the infiltration of peripheral immune cells into the brain in MPTP mice. • Secukinumab inhibits the activation of glial cells and reduces neuroinflammation in MPTP mice.
白细胞介素-17A（IL-17A）与阿尔茨海默病（AD）和帕金森病（PD）等神经退行性疾病的进展有关。然而，美国食品药品监督管理局（FDA）批准的IL-17A抑制剂司库奇尤单抗（SEC）对PD的影响仍不清楚。本研究旨在探讨SEC在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中的神经保护作用及其潜在机制。雄性C57BL/6 J小鼠主要分为三组：假手术组、MPTP组和MPTP + SEC组。使用爬杆试验和转棒试验评估运动协调性。采用免疫组织化学和免疫荧光法评估黑质中的多巴胺能神经元（TH +）和胶质细胞（Iba-1 +、GFAP +）。采用流式细胞术分析脑和脾中的免疫细胞群。使用逆转录聚合酶链反应（RT-PCR）对炎性细胞因子和趋化因子进行定量分析。SEC治疗显著减轻了MPTP小鼠多巴胺能神经元的损失，并改善了运动协调性。它还减少了包括CD4 + T细胞、自然杀伤（NK）细胞和单核细胞-巨噬细胞在内的外周免疫细胞向脑内的浸润。SEC减轻了胶质细胞活化（Iba-1 +、GFAP +），并降低了促炎细胞因子和趋化因子（CCL2、CXCL9）的表达，这些因子可将免疫细胞募集到脑内。这些结果表明，司库奇尤单抗在MPTP诱导的模型中可保护多巴胺能神经元并减轻神经炎症。SEC治疗PD可能是未来临床应用的一种有效治疗方法。要点：• 司库奇尤单抗减少了MPTP小鼠多巴胺能神经元和轴突的损失。• 司库奇尤单抗抑制了MPTP小鼠外周免疫细胞向脑内的浸润。• 司库奇尤单抗抑制了MPTP小鼠胶质细胞的活化并减轻了神经炎症。
