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Dendrobine rescues cognitive dysfunction in diabetic encephalopathy by inhibiting ferroptosis via activating
Yu-Sheng Shi1, Ji-Cong Chen2, Lin Lin3
1Department of Neurology, Center for Cognitive Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou 350001, China; Institute of Clinical Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou 350001, China; Hong Kong Baptist University, Hong Kong 999077, China.
Background:
Ferroptosis playsa crucial role in the development of dementia and dendrobine (Den)possesseshypoglycemic and neuroprotective effects. However, the character of ferroptosis in diabetic encephalopathy (DE) and Den's therapeutic effect remains unclear.
Purpose:
This study aimed to verify the effects of Den on ferroptosis in treating DE and underlying mechanisms.
Study Design:
Den's therapeutic effect was assessed in db/db mice and advanced glycation end products (AGEs)-induced HT22 cells.
Methods:
After oral administration with Den orMetformin for 8-week, behavioral tests were used to assess cognitive capacity. Then, biochemical analysis was preformed to detect glucose and lipid metabolism levels; histological analysis and transmission electron microscope were applied to evaluate pathological injuries. Meanwhile, EdU staining and flow cytometry were applied to test cell apoptosis. Furthermore, mitochondrial dynamics, iron transport, and Nrf2/GPX4 axis related proteins were detected by western blot or immunofluorescence.
Results:
Our results demonstrated that Den remarkably alleviated glucose and lipid metabolism disorders, as well as ameliorated mnemonic deficits of db/db mice. Meanwhile, Den could protect AGEs-induced HT22 cells from death and apoptosis. In addition, we noted that Den inhibited lipid peroxidation by restoring mitochondrial function and reducing reactive oxygen species production. Furthermore, ferroptosis was proven to exist in db/db mice brain and Den could inhibit it via activating Nrf2/GPX4 axis.
Conclusion:
These findings indicated that Den could rescue cognitive dysfunction in DE by inhibiting ferroptosis via activating Nrf2/GPX4 axis.
