Targeting ROS-Dependent AKT/GSK-3β/NF-κB and DJ-1/Nrf2 Pathways by Dapagliflozin Attenuates Neuronal Injury and Motor Dysfunction in Rotenone-Induced Parkinson's Disease Rat Model
Targeting ROS-Dependent AKT/GSK-3β/NF-κB and DJ-1/Nrf2 Pathways by Dapagliflozin Attenuates Neuronal Injury and Motor Dysfunction in Rotenone-Induced Parkinson's Disease Rat Model
复制标题
DOI：
10.1021/acschemneuro.0c00722
复制
发表时间：
2021-02-05
影响因子：
5
通讯作者：
Shahin, Nancy N.
中科院分区：
文献类型：
--
作者：
Arab, Hany H.;Safar, Marwa M.;Shahin, Nancy N.
达格列净是一种选择性钠-葡萄糖共转运蛋白 2 (SGLT2) 抑制剂，通过其显着的抗氧化/抗凋亡特性，在癫痫和肥胖引起的认知障碍小鼠模型中成为一种有前途的神经保护剂。然而，达格列净对帕金森病（PD）发病机制的影响尚不清楚。因此，本研究旨在探讨达格列净对鱼藤酮诱导的 PD 大鼠模型中 PD 相关神经退行性畸变/运动功能障碍的潜在神经保护作用。鱼藤酮 (1.5 mg/kg) 每隔一天皮下注射一次，持续 3 周。使用 qPCR、蛋白质印迹、ELISA 和免疫组织化学研究目标信号的表达。达格列净（1（mg/kg）/天，灌胃 3 周）可减轻 PD 运动功能障碍，改善旷场和旋转测试中的运动协调性，且不会引发低血糖。它还减少了组织病理学改变和α-突触核蛋白表达，并增加了酪氨酸羟化酶和多巴胺水平。达格列净通过降低脂质过氧化物显着减轻神经元氧化应激，从而恢复受干扰的 DJ-1/Nrf2 通路。此外，达格列净可抵消 ROS 依赖性神经元凋亡并上调 GDNF 及其下游 PI3K/AKT/GSK-3 beta (Ser9) 通路。同时，它通过抑制 NF-κ B 通路的激活和 TNF-α 水平来抑制神经炎症。总之，这些多效性神经保护作用凸显了达格列净在 PD 治疗中的前景。
Dapagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has emerged as a promising neuroprotective agent in murine models of epilepsy and obesity-induced cognitive impairment through its marked antioxidant/antiapoptotic features. However, the impact of dapagliflozin on the pathogenesis of Parkinson's disease (PD) is lacking. Hence, the present study aimed at exploring the potential neuroprotective effects of dapagliflozin against PD-associated neurodegenerative aberrations/motor dysfunction in rotenone-induced PD rat model. Rotenone (1.5 mg/kg) was subcutaneously administered every other day for 3 weeks. The expression of target signals was investigated using qPCR, Western blotting, ELISA, and immunohistochemistry. Dapagliflozin (1 (mg/kg)/day, by gavage for 3 weeks) attenuated PD motor dysfunction and improved motor coordination in the open-field and rotarod tests without triggering hypoglycemia. It also diminished the histopathologic alterations and alpha-synuclein expression and augmented tyrosine hydroxylase and dopamine levels. Dapagliflozin markedly alleviated neuronal oxidative stress via lowering lipid peroxides with consequent restoration of the disturbed DJ-1/Nrf2 pathway. Moreover, dapagliflozin counteracted ROS-dependent neuronal apoptosis and upregulated GDNF and its downstream PI3K/AKT/GSK-3 beta (Ser9) pathway. Meanwhile, it suppressed neuroinflammation via curbing the activation of NF-kappa B pathway and TNF-alpha levels. Together, these pleiotropic neuroprotective effects highlight the promising role of dapagliflozin in the management of PD.