Rizk Sara Kamal, Ali Eman A, Sheref AlZahraa A M, Tayel Sara G, El Derbaly Sara A
Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
Immunopharmacol Immunotoxicol. 2025 Jun;47(3):328-344. doi: 10.1080/08923973.2025.2481849. Epub 2025 Mar 25.
Oxidative stress and neuroinflammation are crucial factors in the pathogenesis of Parkinson's disease (PD). Vitamin D (Vit D) and canagliflozin (CAN) are known to have anti-inflammatory and antioxidant properties. Together, they target key molecular pathways involved in PD, including oxidative stress and neuroinflammation, specifically, the small GTPase protein (RAC1)/nuclear factor-kappa B (NF-κB)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which regulates brain's oxidative stress and inflammation. This study investigates the effects of Vit D and CAN alone and in combination in a rat model of PD.
Fifty male Wistar rats were assigned to five groups ( = 10), including control, rotenone (ROT), Vit D + ROT, CAN + ROT, and Vit D + CAN + ROT. We assessed weight changes, brain weight, neurobehavioral functions, biochemical markers, and immunohistopathology of brain tissues.
The results showed that Vit D treatment was more effective than CAN in alleviating PD symptoms, with the combination of Vit D and CAN offering the best therapeutic outcome. This combination therapy significantly improved serum Vit D, striatal dopamine (DA) levels, antioxidant status (reduced glutathione (GSH) and catalase (CAT), reduced oxidative stress (malondialdehyde (MDA)), and ameliorated inflammation (tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10)). Additionally, the combination therapy modulated the expression of RAC1, NF-κB, Nrf2, vitamin D receptors (VDR), and vitamin D-binding protein (DBP) and immunoexpression of tyrosine hydroxylase (TH), and α-synuclein (α-SYN).
These findings suggest that Vit D and CAN synergistically modulate the RAC1/NF-κB/Nrf2 pathway, leading to improved neuroprotection in PD.
氧化应激和神经炎症是帕金森病（PD）发病机制中的关键因素。已知维生素D（Vit D）和卡格列净（CAN）具有抗炎和抗氧化特性。它们共同作用于PD涉及的关键分子途径，包括氧化应激和神经炎症，具体而言，是调节大脑氧化应激和炎症的小GTPase蛋白（RAC1）/核因子-κB（NF-κB）/核因子红细胞2相关因子2（Nrf2）信号通路。本研究调查了Vit D和CAN单独及联合应用对PD大鼠模型的影响。
将50只雄性Wistar大鼠分为五组（每组n = 10），包括对照组、鱼藤酮（ROT）组、Vit D + ROT组、CAN + ROT组和Vit D + CAN + ROT组。我们评估了体重变化、脑重、神经行为功能、生化标志物以及脑组织的免疫组织病理学。
结果表明，Vit D治疗在减轻PD症状方面比CAN更有效，Vit D和CAN联合应用提供了最佳治疗效果。这种联合治疗显著提高了血清Vit D、纹状体多巴胺（DA）水平、抗氧化状态（还原型谷胱甘肽（GSH）和过氧化氢酶（CAT）），降低了氧化应激（丙二醛（MDA）），并改善了炎症（肿瘤坏死因子-α（TNF-α）、白细胞介素6（IL-6）和白细胞介素10（IL-10））。此外，联合治疗调节了RAC1、NF-κB、Nrf2、维生素D受体（VDR）和维生素D结合蛋白（DBP）的表达以及酪氨酸羟化酶（TH）和α-突触核蛋白（α-SYN）的免疫表达。
这些发现表明，Vit D和CAN协同调节RAC1/NF-κB/Nrf2途径，从而在PD中实现更好的神经保护作用。
