Zhi Hui, Wang Xiaoyu, Chen Yujia, Cai Zenglin, Li Jingwei, Guo Dongkai
Department of Pharmacy, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu 215153, P.R. China.
Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu 215002, P.R. China.
Int J Mol Med. 2025 Jun;55(6). doi: 10.3892/ijmm.2025.5526. Epub 2025 Apr 4.
Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is characterized by the death of dopaminergic neurons. It has been reported that ceftriaxone (CEF) exerts promising effects on alleviating dopaminergic neuron death in PD models. However, the neuroprotective mechanisms of CEF in PD have not been well understood. In the present study, to investigate the neuroprotective effects of CEF through western blot and immunofluorescence assays, two models were established, namely the 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑ and lipopolysaccharide (LPS)‑induced models. Additionally, three models were used to explore the neuroprotective mechanisms of CEF, namely the 1‑methyl‑4‑phenylpyridinium ion (MPP+)‑induced dopaminergic neuron injury, LPS‑induced microglia activation and TNFα‑induced astrocyte activation models, with key insights derived from western blot and qPCR experiments. The studies demonstrated that CEF exerted neuroprotective effects and reduced glial cell activation. Additionally, CEF reversed the reduction of tyrosine hydroxylase and suppressed the activation of microglia and astrocytes. Furthermore, the experiments revealed that CEF could display both direct and indirect neuroprotective effects and could directly alleviate MPP+‑induced neuronal toxicity and suppress the activation of microglia and astrocytes. In addition, CEF indirectly reduced neuronal injury caused by conditioned medium from activated microglia and astrocytes. Mechanistic studies revealed that CEF inhibited the ferroptosis pathway via regulating the expression of solute carrier family 7 member 11 and glutathione peroxidase 4 in a non‑cell‑specific manner. Via inhibiting ferroptosis, CEF could directly protect dopaminergic neurons and prevent glial cell activation, and indirectly impair neurons. In conclusion, the results of the current study highlighted the potential research and therapeutic value of CEF in regulating ferroptosis in PD.
帕金森病（PD）是第二常见的神经退行性疾病，其特征是多巴胺能神经元死亡。据报道，头孢曲松（CEF）在帕金森病模型中对减轻多巴胺能神经元死亡具有显著作用。然而，CEF在帕金森病中的神经保护机制尚未完全明确。在本研究中，为通过蛋白质免疫印迹法和免疫荧光测定法研究CEF的神经保护作用，建立了两种模型，即1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导模型和脂多糖（LPS）诱导模型。此外，还使用了三种模型来探究CEF的神经保护机制，即1-甲基-4-苯基吡啶离子（MPP+）诱导的多巴胺能神经元损伤模型、LPS诱导的小胶质细胞激活模型和肿瘤坏死因子α（TNFα）诱导的星形胶质细胞激活模型，并通过蛋白质免疫印迹法和定量聚合酶链反应（qPCR）实验获得关键见解。研究表明，CEF具有神经保护作用，并减少了神经胶质细胞的激活。此外，CEF逆转了酪氨酸羟化酶的减少，并抑制了小胶质细胞和星形胶质细胞的激活。此外，实验表明，CEF可发挥直接和间接的神经保护作用，既能直接减轻MPP+诱导的神经元毒性，又能抑制小胶质细胞和星形胶质细胞的激活。此外，CEF还能间接减轻由活化的小胶质细胞和星形胶质细胞的条件培养基引起的神经元损伤。机制研究表明，CEF通过非细胞特异性方式调节溶质载体家族7成员11和谷胱甘肽过氧化物酶4的表达来抑制铁死亡途径。通过抑制铁死亡，CEF可以直接保护多巴胺能神经元并防止神经胶质细胞激活，间接损伤神经元。总之，本研究结果突出了CEF在调节帕金森病铁死亡方面的潜在研究和治疗价值。
