Magdy Alshimaa, Farrag Eman A E, Hamed Shereen Mohamed, Abdallah Zienab, El Nashar Eman Mohamad, Alghamdi Mansour Abdullah, Ali Amira A H, Abd El-Kader Marwa
Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Department of Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Front Cell Neurosci. 2022 Sep 16;16:967813. doi: 10.3389/fncel.2022.967813. eCollection 2022.
Parkinson's disease (PD) is the second most common neurodegenerative disease. Treatment of PD is challenging, as current treatment strategies are only symptomatic and do not stop disease development. Recent studies reported neuroprotective effects of calcitriol in PD through its antioxidant and anti-inflammatory properties. The exact pathomechanisms of PD are not yet fully understood. So, investigation of different molecular pathways is challenging. Sirtuin-1 (Sirt1) modulates multiple physiological processes, including programmed cell death, DNA repair, and inflammation. Furthermore, defective autophagy is considered a key pathomechanism in PD as it eliminates protein aggregation and dysfunctional cell organelles. The present study investigated the involvement of autophagy and Sirt1/NF-κB molecular pathway in rotenone-induced PD and explored the protective and restorative effects of calcitriol through these mechanisms. Therefore, behavioral tests were used to test the effect of calcitriol on motor disability and equilibrium. Furthermore, the histological and neuronal architecture was assessed. The expression of genes encoding neuroinflammation and autophagy markers was determined by qPCR while their protein levels were determined by Western blot analysis and immune-histochemical staining. Our results indicate that behavioral impairments and dopaminergic neuron depletion in the rotenone-induced PD model were improved by calcitriol administration. Furthermore, calcitriol attenuated rotenone-induced neuroinflammation and autophagy dysfunction in PD rats through up-regulation of Sirt1 and LC3 and down-regulation of P62 and NF-κB expression levels. Thus, calcitriol could induce a neuro-protective and restorative effect in the rotenone-induced PD model by modulating autophagy and Sirt1/NF-κB pathway.
帕金森病（PD）是第二常见的神经退行性疾病。PD的治疗具有挑战性，因为目前的治疗策略只是对症治疗，无法阻止疾病发展。最近的研究报道了骨化三醇通过其抗氧化和抗炎特性对PD具有神经保护作用。PD的确切发病机制尚未完全明确。因此，研究不同的分子途径具有挑战性。沉默调节蛋白1（Sirt1）调节多种生理过程，包括程序性细胞死亡、DNA修复和炎症。此外，自噬缺陷被认为是PD的关键发病机制，因为它能清除蛋白质聚集物和功能失调的细胞器。本研究调查了自噬和Sirt1/NF-κB分子途径在鱼藤酮诱导的PD中的作用，并探讨了骨化三醇通过这些机制产生的保护和恢复作用。因此，采用行为学测试来检测骨化三醇对运动功能障碍和平衡的影响。此外，还评估了组织学和神经元结构。通过qPCR测定编码神经炎症和自噬标志物的基因表达，同时通过蛋白质印迹分析和免疫组织化学染色测定其蛋白质水平。我们的结果表明，给予骨化三醇可改善鱼藤酮诱导的PD模型中的行为障碍和多巴胺能神经元耗损。此外，骨化三醇通过上调Sirt1和LC3以及下调P62和NF-κB表达水平，减轻了鱼藤酮诱导的PD大鼠的神经炎症和自噬功能障碍。因此，骨化三醇可通过调节自噬和Sirt1/NF-κB途径在鱼藤酮诱导的PD模型中产生神经保护和恢复作用。
