Abstract
Hyperglycemia has been widely considered as a key risk factor for diabetic encephalopathy which can cause neuronal apoptosis and cognitive deficits. The flavonoid compound, fisetin, possesses potential neuroprotective effects and also enhances learning and memory. However, the role of fisetin in hyperglycemia-induced neuronal cytotoxicity has not been fully elucidated. In the present study, HT22 murine hippocampal neuronal cell line was used to establish the injured cell model. Cell proliferation and cytotoxicity assay, Hoechst 33258 staining, qRT-PCR, western blot analysis, and specific inhibitor were used to investigate the effect and molecular mechanisms of fisetin on high glucose (HG)-induced neurotoxicity in HT22 cells. Our results showed that 125 μM and 48 h of treatment was identified as optimal damage parameter of HG. Fisetin significantly improved HG-inhibited cell viability. The levels of LDH, malondialdehyde (MDA), and superoxide dismutase (SOD) were noticeably modulated by fisetin, which alleviated HG-induced HT22 cell oxidative damage. Besides, the apoptosis of HT22 cells was rescued by fisetin pretreatment. In addition, fisetin also prevented HG-induced downregulation of the mRNA expression of Bdnf, Gdnf, synaptophysin (Syp), and glutamate ionotropic receptor AMPA type subunit 1 (Gria1) in cells. More importantly, the decreased phosphorylation of phosphoinositide 3 kinase (PI3K), Akt, and cAMP-response element binding protein (CREB) was rescued by fisetin treatment and that neuroprotective effect of fisetin was partially blocked by PI3K inhibitor, LY294002. These findings indicate that fisetin has potent neuroprotective effect and prevents HG-induced neurotoxicity by activation of PI3K/Akt/CREB pathway.
Highlights
Diabetic encephalopathy is one of the most common crippling complications resulting from diabetes mellitus (DM) affecting central nervous system (Zenker et al, 2013; Simo et al, 2017)
We investigated the neuroprotective effect of fisetin on high glucose (HG)-induced cell apoptosis in HT22 cells, and whether fisetin protected HT22 cells against HGinduced neurotoxicity via phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/cAMP-response element binding protein (CREB) signaling pathway would be studied
We found the involvement of the PI3K/Akt/CREB signaling in the protection effect of fisetin on HG-induced HT22 cell injury
Summary
Diabetic encephalopathy is one of the most common crippling complications resulting from diabetes mellitus (DM) affecting central nervous system (Zenker et al, 2013; Simo et al, 2017). Accumulated evidences have demonstrated that DM patients have a significantly higher risk of suffering from cognitive dysfunction (Biessels et al, 2006; Biessels and Despa, 2018). Several prospective studies have shown that high blood glucose level is a key risk factor in DM-induced cognitive dysfunction and dementia (Kaeidi et al, 2019; Zhang et al, 2019; Sharma et al, 2020). The neuronal glucose level in the central nervous system can be induced up to four-fold increase by hyperglycemia in diabetes (Zhu et al, 2018). The abnormal intracellular glucose metabolism possesses multiple toxic effects on brain, such as formation of advanced glycated end products (AGEs), generation of ROS, and activation of polyol, diacylglycerol, and hexosamine pathways, leading to cognitive dysfunction (Seto et al, 2015). Therapeutically targeting hyperglycemia-induced damage of nerve cells and explicit the molecular mechanism would be a novel strategy for treating diabetic neuropathy
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