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

Xuan Kang; Cheng Li; Yan Xie; Ling-Li He; Fan Xiao; Ke-Bin Zhan; Yi-Yun Tang; Xiang Li; Xiao-Qing Tang

doi:10.1016/j.jare.2020.06.007

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

J Adv Res. 2020 Jun 12:27:31-40. doi: 10.1016/j.jare.2020.06.007. eCollection 2021 Jan.

Authors

Xuan Kang^{1

2}, Cheng Li^{3

4}, Yan Xie⁴, Ling-Li He⁴, Fan Xiao², Ke-Bin Zhan⁴, Yi-Yun Tang², Xiang Li⁵, Xiao-Qing Tang^{1

2}

Affiliations

¹ Institute of Neurology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, PR China.
² Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang 421001, Hunan, PR China.
³ Department of Emergency Affiliated Nanhua Hospital, University of South China, Hengyang 421001, Hunan, PR China.
⁴ Department of Neurology, The Second Affiliated Hospital, University of South China, Hengyang 421001, Hunan, PR China.
⁵ Department of Anesthesiology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, PR China.

Abstract

Introduction: 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.

Objectives: To investigate the roles of hippocampal ODC/Spd pathway and autophagic flux in H2S-attenuated cognitive impairment in STZ-induced diabetic rats.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Autophagic flux; Cognitive impairment; Diabetes; Hydrogen sulfide; Ornithine decarboxylase/spermidine pathway.

Publication types

Review