Center for Diabetes, Obesity and Metabolism, Department of Physiology, School of Basic Medical Sciences , Shenzhen University Health Sciences Center , Shenzhen , Guangdong 518060 , China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center , Sun Yat-Sen University , Guangzhou , Guangdong 510064 , China.
J Agric Food Chem. 2019 Jul 31;67(30):8348-8360. doi: 10.1021/acs.jafc.9b02954. Epub 2019 Jul 19.
We have recently demonstrated that tau hyperphosphorylation causes diabetic synaptic neurodegeneration of retinal ganglion cells (RGCs), which might be the earliest affair during the pathogenesis of diabetic retinopathy (DR). Thus, there is a pressing need to seek therapeutic agents possessing neuroprotective effects against tau hyperphosphorylation in RGCs for arresting the progression of DR. Here, using a well-characterized diabetes model of / mouse, we discovered that topical ocular application of 10 mg/kg/day of ginsenoside Rg1 (GRg1), one of the major active ingredients extracted from and , ameliorated hyperphosphorylated tau-triggered RGCs synaptic neurodegeneration in diabetic mice. The neuroprotective effects of GRg1 on diabetic retinae were abrogated when retinal IRS-1 or Akt was suppressed by intravitreal injection with si- or topically coadministered with a specific inhibitor of Akt, respectively. However, selective repression of retinal GSK3β by intravitreal administration of si- rescued the neuroprotective properties of GRg1 when Akt was inactivated. Therefore, the present study showed for the first time that GRg1 can prevent hyperphosphorylated tau-induced synaptic neurodegeneration of RGCs via activation of IRS-1/Akt/GSK3β signaling in the early phase of DR. Moreover, our data clarify the potential therapeutic significance of GRg1 for neuroprotective intervention strategies of DR.
我们最近证明，tau 过度磷酸化导致糖尿病视网膜神经节细胞（RGCs）的突触神经退行性变，这可能是糖尿病性视网膜病变（DR）发病机制中的最早事件。因此，迫切需要寻找具有针对 RGCs 中 tau 过度磷酸化的神经保护作用的治疗剂，以阻止 DR 的进展。在这里，我们使用一种经过充分表征的糖尿病 / 小鼠模型，发现每天局部眼部应用 10 mg/kg 的人参皂苷 Rg1（GRg1），一种从 和 中提取的主要活性成分之一，可以改善糖尿病小鼠中 tau 过度磷酸化引发的 RGCs 突触神经退行性变。当通过眼内注射 siRNA 或局部共给予 Akt 的特异性抑制剂抑制视网膜 IRS-1 或 Akt 时，GRg1 对糖尿病视网膜的神经保护作用被消除。然而，当 Akt 失活时，通过眼内注射 siRNA 选择性抑制视网膜 GSK3β 可挽救 GRg1 的神经保护特性。因此，本研究首次表明，GRg1 可以通过激活 DR 早期的 IRS-1/Akt/GSK3β 信号通路来预防 tau 过度磷酸化诱导的 RGCs 突触神经退行性变。此外，我们的数据阐明了 GRg1 用于 DR 神经保护干预策略的潜在治疗意义。
