Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, 160 014, India.
Metab Brain Dis. 2021 Oct;36(7):1833-1857. doi: 10.1007/s11011-021-00811-7. Epub 2021 Aug 7.
The present study investigates the neuro-protective ability of nordihydroguaretic acid (NDGA) in the experimental paradigm of autism spectrum disorders (ASD) and further decipher the nitric oxide pathway's role in its proposed action. An intracerebroventricular infusion of 4 μl of 1 M PPA was given in the lateral ventricle's anterior region to induce autism-like phenotype in male rats. Oral administration of NDGA (5, 10 & 15 mg/kg) was initiated from the 3 day lasting till the 28th day. L-NAME (50 mg/kg) and L-Arginine (800 mg/kg) were also given individually and combined to explore NDGA's ability to act via the nitric oxide pathway. Behavior tests for sociability, stereotypy, anxiety, depression, novelty, repetitive and perseverative behavior were carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To assess the involvement of the nitric oxide pathway, levels of iNOS and homocysteine were estimated. Treatment with NDGA significantly restored behavioral, biochemical, neurological, and molecular deficits. Hence, NDGA can be used as a neurotherapeutic agent in ASD. Targeting nitric oxide pathway mediated oxidative & nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. The evaluation of iNOS and homocysteine levels conclusively establishes the nitric oxide pathway's role in causing behavioral, biochemical & molecular deficits and NDGA's beneficial effect in restoring these alterations.
本研究探讨了去甲二氢愈创木酸（NDGA）在自闭症谱系障碍（ASD）实验模型中的神经保护能力，并进一步解析了一氧化氮途径在其作用机制中的作用。在侧脑室前区域给予 4μl 1M PPA 的脑室内注射，以诱导雄性大鼠产生类似自闭症的表型。从第 3 天持续到第 28 天，给予 NDGA（5、10 和 15mg/kg）口服给药。还单独给予 L-NAME（50mg/kg）和 L-精氨酸（800mg/kg），并将其组合以探索 NDGA 经由一氧化氮途径发挥作用的能力。在第 14 天至第 28 天之间进行社交、刻板、焦虑、抑郁、新奇、重复和固执行为的行为测试。第 29 天，处死动物，评估线粒体复合物和氧化应激参数。我们还评估了神经炎症和细胞凋亡标志物如 TNF-α、IL-6、NF-κB、IFN-γ、HSP-70 和 caspase-3 的水平。为了评估一氧化氮途径的参与，还估计了 iNOS 和同型半胱氨酸的水平。NDGA 的治疗显著恢复了行为、生化、神经和分子缺陷。因此，NDGA 可作为 ASD 的神经治疗剂。通过调节一氧化氮途径，靶向一氧化氮途径介导的氧化和硝化应激，负责行为、生化和分子改变。iNOS 和同型半胱氨酸水平的评估最终确立了一氧化氮途径在引起行为、生化和分子缺陷中的作用，以及 NDGA 在恢复这些改变中的有益作用。
