Abstract
Diabetic encephalopathy (DE) is a serious complication caused by long-term cognitive impairment in diabetic patients. At present, there is no effective treatment for DE. Icariin (ICA) is a bioactive ingredient isolated from Epimedium. Previous research indicated that ICA was neuroprotective against Aβ-induced PC12 cell insult; however, the effect of ICA on an advanced glycosylation end product- (AGE-) induced neural injury model has not been studied. In this study, we investigated the neuroprotective effects of ICA on AGE-induced injury in PC12 cells. Our findings revealed that ICA could effectively protect PC12 cells from AGE-induced cell apoptosis by suppressing oxidative stress. Moreover, we observed that ICA could significantly protect against mitochondrial depolarization following AGE stimulation and inactivate the mitochondria-dependent caspase-9/3 apoptosis pathway. Most notably, we identified the direct target protein of ICA as apoptosis regulator Bax by a pulldown assay. We found that ICA could specifically target Bax protein and inhibit Bax dimer formation and migration to mitochondria. Furthermore, a siRNA knockdown experiment revealed that ICA could inhibit PC12 cell apoptosis and oxidative stress through targeting Bax. Taken together, our findings demonstrated that ICA could attenuate AGE-induced oxidative stress and mitochondrial apoptosis by specifically targeting Bax and further regulating the biological function of Bax on mitochondria.
Highlights
Diabetes mellitus (DM) is a common metabolic disease
We found that advanced glycosylation end products (AGEs) (300 μg/mL) stimulation for 48 h markedly facilitated lactate dehydrogenase (LDH) release from PC12 cells, which was four times as much as the control group (P < 0 001)
All of these results suggested that AGEs significantly induced PC12 cell apoptosis, and ICA could protect PC12 cells from AGE insult
Summary
Diabetes mellitus (DM) is a common metabolic disease. In the development of DM, a variety of complications can be formed, of which diabetic encephalopathy (DE) is a major central nervous system complication. The pathogenesis of DE is still not clear, recent studies have found that overproduction of advanced glycosylation end products (AGEs) is closely related to the occurrence of DE [4, 5]. AGEs are toxic substances produced by nonenzymatic glycosylation of proteins and reducing sugars under long-term hyperglycemia. It is important to develop drugs that inhibit oxidative stress induced by AGEs in neurons. AGEs can induce oxidative stress and reactive oxygen species (ROS) formation, leading to cell damage and even apoptosis [10,11,12]
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