Neuroprotective effects of ginsenoside Rg1 against hyperphosphorylated tau-induced diabetic retinal neurodegeneration via activation of IRS-1/Akt/GSK3β signaling.
Neuroprotective effects of ginsenoside Rg1 against hyperphosphorylated tau-induced diabetic retinal neurodegeneration via activation of IRS-1/Akt/GSK3β signaling.
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DOI：
10.1021/acs.jafc.9b02954
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发表时间：
2019-07
影响因子：
6.1
通讯作者：
Y. Ying;Yi-lin Zhang;Canjie Ma;Meiqi Li;Chao-Yue Tang;Yangfan Yang;Jun-hui Zeng;Xiao-yan Huang;Junbo Yi;Xiaomei Wang;Zhen-Dan He;Xingsheng Shu
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作者：
Y. Ying;Yi-lin Zhang;Canjie Ma;Meiqi Li;Chao-Yue Tang;Yangfan Yang;Jun-hui Zeng;Xiao-yan Huang;Junbo Yi;Xiaomei Wang;Zhen-Dan He;Xingsheng Shu
我们最近发现tau蛋白过度磷酸化导致糖尿病视网膜神经节细胞（retinal ganglion cells，RGC）的突触神经变性，这可能是糖尿病视网膜病变（diabetic retinopathy，DR）发病过程中最早的事件。因此，迫切需要寻找具有针对RGC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。在此，使用良好表征的db/db小鼠糖尿病模型，我们发现局部眼部应用10 mg/kg/天的从人参和三七中提取的主要活性成分之一的GRG 1（GRg 1），改善糖尿病小鼠中过度磷酸化tau触发的RGCs突触神经变性。当视网膜IRS-1或Akt分别通过玻璃体内注射si-IRS-1或局部联合施用Akt的特异性抑制剂来抑制时，GRg 1对糖尿病视网膜的神经保护作用被废除。然而，当Akt失活时，通过玻璃体内施用si-GSK 3 β选择性抑制视网膜GSK 3 β拯救了GRg 1的神经保护特性。因此，本研究首次发现GRg 1在DR早期通过激活IRS-1/Akt/GSK 3 β信号通路阻止过度磷酸化tau蛋白诱导的RGCs突触神经元变性，并阐明了GRg 1在DR神经保护干预策略中的潜在治疗意义。
We have recently demonstrated that tau hyperphosphorylation causes diabetic synaptic neurodegeneration of retinal ganglion cells (RGCs), which might be the earliest event during the pathogenesis of diabetic retinopathy (DR). Thus, there is a pressing need to search for therapeutic agents possessing neuroprotective effects against tau hyperphosphorylation in RGCs for arresting the progression of DR. Here, using a well characterized diabetes model of db/db mouse, we discovered that topical ocular application of 10 mg/kg/day of ginsenoside Rg1 (GRg1), one of the major active ingredients extracted from Panax ginseng and Panax notoginseng, 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-IRS-1 or topically co-administration with a specific inhibitor of Akt, respectively. However, selective repression of retinal GSK3β by intravitreal administration of si-GSK3β 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.