Hippocampal ornithine decarboxylase/spermidine pathway mediates H2S-alleviated cognitive impairment in diabetic rats: Involving enhancment of hippocampal autophagic flux

• Published in: Journal of advanced research 2021-01, Vol.27, p.31-40
• Main Authors: Kang, Xuan, Li, Cheng, Xie, Yan, He, Ling-Li, Xiao, Fan, Zhan, Ke-Bin, Tang, Yi-Yun, Li, Xiang, Tang, Xiao-Qing
• Format: Article
• Language: English
• Subjects: Autophagic flux; Cognitive impairment; Diabetes; Hydrogen sulfide; Ornithine decarboxylase/spermidine pathway
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2020.06.007

[Display omitted] We have previously demonstrated the antagonistic role of hydrogen sulfide (H2S) in the cognitive dysfunction of streptozotocin (STZ)-induced diabetic rats. It has been confirmed that the impaired hippocampal autophagic flux has a key role in the pathogenesis of cognitive impairment and that ornithine decarboxylase (ODC)/spermidine (Spd) pathway plays an important role in the formation of memory by promoting autophagic flux. To investigate the roles of hippocampal ODC/Spd pathway and autophagic flux in H2S-attenuated cognitive impairment in STZ-induced diabetic rats. Cognitive function is judged by the novel objective recognition task (NOR), the Y-maze, and the Morris water maze (MWM) tests. The ODC/Spd pathway in hippocampus was evaluated using the expression of ODC detected by western blot and the level of Spd assayed by GC-MS. Autophagic flux was assessed using the expressions of Beclin-1, LC3II/I, and P62 detected by western blot, and the number of autophagosomes observed by transmission electron microscope. Sodium hydrosulfide (NaHS, a donor of H2S) markedly improved the autophagic flux in the hippocampus of STZ-exposed rats, as evidenced by a decrease in the number of autophagosomes as wells as downregulations in the expressions of LC3-II, Beclin-1, and P62 in the hippocampus of cotreatment with NaHS and STZ rats. NaHS also up-regulated the expression of ODC and the level of Spd in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited hippocampal ODC/Spd pathway by difluoromethylornithine (DFMO) markedly reversed the protections of NaHS against the hippocampal autophagic flux impairment as well as the cognitive dysfunction in STZ-exposed rats. These findings indicated that improving hippocampal autophagic flux plays a key role in H2S-attenuated cognitive impairment in STZ-induced diabetic rats, as results of up-regulating hippocampal ODC/Spd pathway.