Department of Neuroscience, School of Medicine of Ribeirão Preto, University of São Paulo, SP, 14040-900, Brazil.
Department of Morphology, Physiology and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, 14040-904, Brazil.
Neurotox Res. 2021 Jun;39(3):705-719. doi: 10.1007/s12640-021-00345-x. Epub 2021 Mar 9.
Interferon-γ (IFN-γ) is a proinflammatory cytokine that activates glial cells. IFN-γ is increased in the plasma and brain of Parkinson's disease patients, suggesting its potential role in the disease. We investigated whether the IFN-γ deficiency could interfere with nigrostriatal degeneration induced by the neurotoxin 6-hydroxydopamine, L-DOPA-induced dyskinesia, and the neuroinflammatory features as astrogliosis, microgliosis, and induced nitric oxide synthase (iNOS) immunoreactivity induced by L-DOPA treatment. Wild type (WT) and IFN-γ knockout (IFN-γ/KO) mice received unilateral striatal microinjections of 6-hydroxydopamine. Animals were sacrificed 1, 3, 7, and 21 days after lesions. Additional group of WT and IFN-γ/KO parkinsonian mice, after 3 weeks of neurotoxin injection, received L-DOPA (intraperitoneally, for 21 days) resulting in dyskinetic-like behavior. Tyrosine hydroxylase immunostaining indicated the starting of dopaminergic lesion since the first day past toxin administration, progressively increased until the third day when it stabilized. There was no difference in the lesion and L-DOPA-induced dyskinesia intensity between WT and IFN-γ/KO mice. Remarkably, IFN-γ/KO mice treated with L-DOPA presented in the lesioned striatum an increase of iNOS and glial fibrilary acid protein (GFAP) density, compared with the WT group. Morphological analysis revealed the rise of astrocytes and microglia reactivity in IFN-γ/KO mice exibiting dyskinesia. In conclusion, IFN-γ/KO mice presented an intensification of the inflammatory reaction accompanying L-DOPA treatment and suggest that iNOS and GFAP increase, and the activation of astrocytes and microglia induced afterward L-DOPA treatment was IFN-γ independent events. Intriguingly, IFN-γ absence did not affect the degeneration of dopaminergic neurons or LID development.
干扰素-γ（IFN-γ）是一种促炎细胞因子，可激活神经胶质细胞。帕金森病患者的血浆和大脑中 IFN-γ 增加，表明其在疾病中的潜在作用。我们研究了 IFN-γ 缺乏是否会干扰神经毒素 6-羟多巴胺诱导的黑质纹状体变性、L-多巴诱导的运动障碍以及 L-多巴治疗诱导的神经炎症特征，如星形胶质细胞增生、小胶质细胞增生和诱导型一氧化氮合酶（iNOS）免疫反应。野生型（WT）和 IFN-γ 敲除（IFN-γ/KO）小鼠接受单侧纹状体微量注射 6-羟多巴胺。动物在损伤后 1、3、7 和 21 天处死。另一组 WT 和 IFN-γ/KO 帕金森病小鼠在神经毒素注射 3 周后接受 L-多巴（腹腔内，21 天），导致运动障碍样行为。酪氨酸羟化酶免疫染色表明多巴胺能损伤自毒素给药后第一天开始，直到第三天稳定时逐渐增加。WT 和 IFN-γ/KO 小鼠的损伤和 L-多巴诱导的运动障碍强度没有差异。值得注意的是，与 WT 组相比，用 L-多巴治疗的 IFN-γ/KO 小鼠损伤纹状体中的 iNOS 和神经胶质纤维酸性蛋白（GFAP）密度增加。形态分析显示，在出现运动障碍的 IFN-γ/KO 小鼠中，星形胶质细胞和小胶质细胞反应性增加。总之，IFN-γ/KO 小鼠在接受 L-多巴治疗时表现出炎症反应加剧，并表明 iNOS 和 GFAP 增加，并且 L-多巴治疗后星形胶质细胞和小胶质细胞的激活是 IFN-γ 独立的事件。有趣的是，IFN-γ 缺失不会影响多巴胺能神经元的变性或 LID 的发展。
