Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre 90035-003, RS, Brazil.
Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Cells. 2023 Jun 6;12(12):1557. doi: 10.3390/cells12121557.
Sulfite predominantly accumulates in the brain of patients with isolated sulfite oxidase (ISOD) and molybdenum cofactor (MoCD) deficiencies. Patients present with severe neurological symptoms and basal ganglia alterations, the pathophysiology of which is not fully established. Therapies are ineffective. To elucidate the pathomechanisms of ISOD and MoCD, we investigated the effects of intrastriatal administration of sulfite on myelin structure, neuroinflammation, and oxidative stress in rat striatum. Sulfite administration decreased Fluoromyelin and myelin basic protein staining, suggesting myelin abnormalities. Sulfite also increased the staining of NG2, a protein marker of oligodendrocyte progenitor cells. In line with this, sulfite also reduced the viability of MO3.13 cells, which express oligodendroglial markers. Furthermore, sulfite altered the expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1), indicating neuroinflammation and redox homeostasis disturbances. Iba1 staining, another marker of neuroinflammation, was also increased by sulfite. These data suggest that myelin changes and neuroinflammation induced by sulfite contribute to the pathophysiology of ISOD and MoCD. Notably, post-treatment with bezafibrate (BEZ), a pan-PPAR agonist, mitigated alterations in myelin markers and Iba1 staining, and IL-1β, IL-6, iNOS and HO-1 expression in the striatum. MO3.13 cell viability decrease was further prevented. Moreover, pre-treatment with BEZ also attenuated some effects. These findings show the modulation of PPAR as a potential opportunity for therapeutic intervention in these disorders.
亚硫酸盐主要在孤立性亚硫酸盐氧化酶 (ISOD) 和钼辅因子 (MoCD) 缺乏症患者的大脑中积累。患者表现出严重的神经症状和基底节改变，其病理生理学尚未完全确定。治疗方法无效。为了阐明 ISOD 和 MoCD 的发病机制，我们研究了亚硫酸盐在大鼠纹状体中的脑内给药对髓鞘结构、神经炎症和氧化应激的影响。亚硫酸盐给药降低了 Fluoromyelin 和髓鞘碱性蛋白的染色，表明髓鞘异常。亚硫酸盐还增加了 NG2 的染色，NG2 是少突胶质细胞前体细胞的一种蛋白标志物。与此一致，亚硫酸盐还降低了表达少突胶质细胞标志物的 MO3.13 细胞的活力。此外，亚硫酸盐改变了白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6)、白细胞介素-10 (IL-10)、环加氧酶-2 (COX-2)、诱导型一氧化氮合酶 (iNOS) 和血红素加氧酶-1 (HO-1) 的表达，表明神经炎症和氧化还原平衡紊乱。亚硫酸盐还增加了另一种神经炎症标志物 Iba1 的染色。这些数据表明，亚硫酸盐引起的髓鞘变化和神经炎症导致了 ISOD 和 MoCD 的病理生理学。值得注意的是，泛 PPAR 激动剂 bezafibrate (BEZ) 的治疗后减轻了纹状体中髓鞘标志物和 Iba1 染色的改变，以及 IL-1β、IL-6、iNOS 和 HO-1 的表达。MO3.13 细胞活力的下降也得到了进一步的预防。此外，BEZ 的预处理也减轻了一些影响。这些发现表明，PPAR 的调节可能是这些疾病治疗干预的一个潜在机会。
