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

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 expres-sion 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 hip-pocampus 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 hippocam-pus of STZ-induced diabetic rats. Furthermore, inhibited hippocampal ODC/Spd pathway by difluo-romethylornithine (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 hippocam-pal ODC/Spd pathway. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of Cairo University.