Habib Mohamed Z, Tadros Mariane G, Abd-Alkhalek Hadwa A, Mohamad Magda I, Eid Dalia M, Hassan Fatma E, Elhelaly Hend, Faramawy Yasser El, Aboul-Fotouh Sawsan
Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Eur J Pharmacol. 2022 Jul 15;927:175046. doi: 10.1016/j.ejphar.2022.175046. Epub 2022 May 25.
Oxidative stress induced neurotoxicity is increasingly perceived as an important neuropathologic mechanism underlying the motor and behavioral phenotypes associated with Huntington's disease (HD). Repeated exposure to 3-nitropropionic acid (3-NP) induces neurotoxic changes which closely simulate the neuropathological and behavioral characteristics of HD. This study aimed at evaluating the prophylactic effects of the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitor "harmine" against 3-NP-indued neurotoxicity and HD-like symptoms. The potential prophylactic effect of harmine (10 mg/kg/day; intraperitoneal) was investigated on 3-NP-induced motor and cognitive HD-like deficits, nuclear factor erythroid 2 like 2 (NRF2), AMP kinase (AMPK) and p21 protein levels and the gene expression of haem oxygenase-1 (Ho-1), NAD(P)H: quinone oxidoreductase-1 (Nqo-1) and p62 in addition to redox imbalance and histological neurotoxic changes in the striatum, prefrontal cortex, and hippocampus of male Wistar rats. Harmine successfully increased the protein levels of NRF2, AMPK and p21 and the gene expression of Ho-1, Nqo-1 and p62, restored redox homeostasis, and reduced CASPASE-3 level. This was reflected in attenuation of 3-NP-induced neurodegenerative changes and improvement of rats' motor and cognitive performance. This study draws attention to the protective role of harmine against 3-NP-induced motor and cognitive dysfunction that could be mediated via enhancing NRF2-mediated signaling with subsequent amelioration of oxidative stress injury via NRF2 activators, p21 and AMPK, in the striatum, prefrontal cortex, and hippocampus which could offer a promising therapeutic tool to slow the progression of HD.
氧化应激诱导的神经毒性越来越被认为是亨廷顿舞蹈病（HD）相关运动和行为表型背后的一种重要神经病理机制。反复接触3-硝基丙酸（3-NP）会诱导神经毒性变化，这与HD的神经病理学和行为特征极为相似。本研究旨在评估双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）抑制剂“哈尔明”对3-NP诱导的神经毒性和HD样症状的预防作用。研究了哈尔明（10毫克/千克/天；腹腔注射）对3-NP诱导的运动和认知HD样缺陷、核因子红细胞2样2（NRF2）、AMP激酶（AMPK）和p21蛋白水平以及血红素加氧酶-1（Ho-1）、NAD（P）H：醌氧化还原酶-1（Nqo-1）和p62基因表达的潜在预防作用，此外还研究了其对雄性Wistar大鼠纹状体、前额叶皮质和海马体中氧化还原失衡和组织学神经毒性变化的影响。哈尔明成功提高了NRF2、AMPK和p21的蛋白水平以及Ho-1、Nqo-1和p62的基因表达，恢复了氧化还原稳态，并降低了CASPASE-3水平。这体现在3-NP诱导的神经退行性变化的减轻以及大鼠运动和认知能力的改善上。本研究提请注意哈尔明对3-NP诱导的运动和认知功能障碍的保护作用，这可能是通过增强NRF2介导的信号传导，随后通过NRF2激活剂、p21和AMPK改善纹状体、前额叶皮质和海马体中的氧化应激损伤来实现的，这可能为减缓HD的进展提供一种有前景的治疗工具。
