Al-Garni Abdulaziz M, Hosny Sara A, Almasabi Faris, Shati Ayed A, Alzamil Norah M, ShamsEldeen Asmaa M, El-Shafei Asmaa A, Al-Hashem Fahaid, Zafrah Hind, Maarouf Amro, Al-Ani Bahjat, Bin-Jaliah Ismaeel, Kamar Samaa S
Psychiatry section, Department of Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Department of Psychiatry, School of Medicine, Queen's University, Kingston, Ontario, Canada.
PLoS One. 2025 Feb 13;20(2):e0317695. doi: 10.1371/journal.pone.0317695. eCollection 2025.
Autism spectrum disorder (ASD) is a collective neurodevelopmental disorder affecting young children and accounting for 1% of the world's population. The cerebellum is the major part of the human brain affected by ASD and is associated with a substantial reduction in the number of Purkinje cells. An association between ASD and the expression of the nitrosative stress biomarker inducible nitric oxide synthase (iNOS), as well as glycogen deposition in damaged Purkinje cells, has not been previously reported in the medical literature. To explore this correlation, young rats were injected with propionic acid (PPA) (500 mg/kg) for 5 days (model group), while the protection groups were treated with either erythropoietin (EPO, 5,000 U/kg) or 2 mg/kg zinc sulfate immediately after the PPA injections. ASD-like features were developed in the model group, as evidenced by cerebellum damage (degeneration of Purkinje cells) and cerebellar dysfunction (behavioral impairment). This study documented the exclusive expression of iNOS in the degenerated Purkinje cells, along with glycogen deposition in these cells. Additionally, PPA significantly (p < 0.001) modulated cerebellar tissue levels of mammalian target of rapamycin (mTOR), gamma-aminobutyric acid (GABA), GABAA receptor, serotonin, the marker of neuronal loss (calbindin D28K), and social interaction deficit. Some of these parameters were differentially protected by EPO and zinc sulfate, with the former providing greater protection than zinc sulfate. Furthermore, a significant correlation between the iNOS score and these parameters associated with ASD was observed. These findings demonstrate the colocalization of iNOS and glycogen in the damaged Purkinje cells induced by ASD, along with the modulation of ASD parameters, which were protected by EPO and zinc sulfate treatments. Thus, these potential novel biomarkers may offer possible therapeutic targets for the treatment of ASD.
自闭症谱系障碍（ASD）是一种影响幼儿的神经发育障碍，占全球人口的1%。小脑是受ASD影响的人类大脑主要部分，与浦肯野细胞数量大幅减少有关。医学文献中此前尚未报道ASD与亚硝化应激生物标志物诱导型一氧化氮合酶（iNOS）的表达以及受损浦肯野细胞中糖原沉积之间的关联。为了探究这种相关性，给幼鼠注射丙酸（PPA）（500mg/kg），持续5天（模型组），而保护组在注射PPA后立即用促红细胞生成素（EPO，5000U/kg）或2mg/kg硫酸锌进行治疗。模型组出现了类似ASD的特征，表现为小脑损伤（浦肯野细胞退化）和小脑功能障碍（行为损害）。本研究记录了iNOS在退化的浦肯野细胞中的特异性表达，以及这些细胞中的糖原沉积。此外，PPA显著（p<0.001）调节了小脑组织中雷帕霉素哺乳动物靶点（mTOR）、γ-氨基丁酸（GABA）、GABAA受体、血清素、神经元丢失标志物（钙结合蛋白D28K）的水平以及社交互动缺陷。其中一些参数受到EPO和硫酸锌的不同程度保护，前者提供的保护比硫酸锌更大。此外，观察到iNOS评分与这些与ASD相关的参数之间存在显著相关性。这些发现表明，iNOS和糖原在ASD诱导的受损浦肯野细胞中共定位，同时ASD参数受到调节，而EPO和硫酸锌治疗可对其起到保护作用。因此，这些潜在的新型生物标志物可能为ASD的治疗提供可能的治疗靶点。
