Department of Biological Sciences/Neuroscience Program, Delaware State University, Dover, DE 19901, USA.
Seoul Center, Korea Basic Science Institute, Seongbuk-gu, Seoul 02841, Republic of Korea.
Int J Mol Sci. 2023 Sep 19;24(18):14278. doi: 10.3390/ijms241814278.
Oxidative stress-mediated damage is often a downstream result of Parkinson's disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD.
氧化应激介导的损伤通常是帕金森病 (PD) 的下游结果，其特征是大脑黑质纹状体区域的多巴胺能神经元急剧减少，导致患者出现运动症状缺陷。调节氧化应激水平可能是预防 PD 病理的一种有益方法。在这里，我们评估了烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶 (NOX) 抑制剂的疗效，这是 Aptabio 治疗公司合成的一种外源性活性氧 (ROS) 调节剂，对 NOX-1、2 和 4 具有特异性。利用 N27 大鼠多巴胺能细胞和 C57Bl/6 小鼠，我们证实了 α-突触核蛋白原纤维 (PFF) 的暴露诱导了蛋白质聚集，这是 PD 病理的一个标志。对新型化合物的体外评估显示，在最佳浓度 10 nM 时，与 PFF 暴露相比，细胞活力增加，细胞毒性、ROS 和蛋白质聚集（硫黄素-T 染色）减少。同时，口服治疗通过减少蛋白质聚集，减轻了行为测试中的运动缺陷，如后肢扣状、转棒、棒状、嵌套和梳理测试，这是基于多巴胺能神经元损失的挽救。纹状体和腹侧中脑区域（包括黑质致密部 (SNc)）中 NOX-1、2 和 4 的抑制有助于神经保护/恢复作用，使其成为 PD 的潜在治疗选择。
