Cellular, Molecular and Developmental NeuroscienceSpermidine inhibits high glucose-induced endoplasmic reticulum stress in HT22 cells by upregulation of growth differentiation factor 11Liao, Zhou-Zana,*; Deng, Qia,*; Xiao, Fanb; Xie, Minga; Tang, Xiao-Qinga,b Author Information aThe First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China bKey Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang, P.R. China Received 19 August 2022 Accepted 16 October 2022. *Zhou-Zan Liao and Qi Deng contributed equally to the writing of this article. Correspondence to Dr. Xiao-Qing Tang, The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, 69 Chuanshan Road, Hengyang, 421001, Hunan, P. R. China, Tel: +8615973411737; e-mail: [email protected] NeuroReport: December 14, 2022 - Volume 33 - Issue 18 - p 819-827 doi: 10.1097/WNR.0000000000001853 Buy Metrics Abstract Hyperglycemia-induced neuronal endoplasmic reticulum (ER) stress is particularly important for the pathogenesis of diabetic encephalopathy. Spermidine (Spd) has neuroprotection in several nervous system diseases. Our current study to explore the potential protective role of Spd in hyperglycemia-induced neuronal ER stress and the underlying mechanisms. HT22 cells were treated with high glucose (HG) to establish an in-vitro model of hyperglycemia toxicity. The HT22 cells’ activity was tested by cell counting kit-8 assay. RNA interference technology was used to silence the expression of growth differentiation factor 11 (GDF11) in HT22 cells. The GDF11 expression levels of mRNA were assessed using reverse transcription-PCR (RT-PCR). Western blotting analysis was applied to evaluate the expressions of GRP78 and cleaved caspase-12. Spd markedly abolished HG-exerted decline in cell viability as well as upregulations of GRP78 and cleaved caspase-12 in HT22 cells, indicating the protection of Spd against HG-induced neurotoxicity and ER stress. Furthermore, we showed that Spd upregulated the expression of GDF11 in HG-exposed HT22 cells. While, silenced GDF11 expression by RNA interference reversed the protective effects of Spd on HG-elicited neurotoxicity and ER stress in HT22 cells. These results indicated that Spd prevents HG-induced neurotoxicity and ER stress through upregulation of GDF11. Our findings identify Spd as a potential treatment for diabetic encephalopathy as well as ER stress-related neurologic diseases. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.