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

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.
Xuan Kang 1 2,  Cheng Li 3 4,  Yan Xie 4,  Ling-Li He 4,  Fan Xiao 2,  Ke-Bin Zhan 4,  Yi-Yun Tang 2,  Xiang Li 5,  Xiao-Qing Tang 1 2
Affiliations

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.
PMID: 33318864 DOI: 10.1016/j.jare.2020.06.007
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.

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