Background: Hypoxia can suppress neural activities and cause cognitive impairment. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor expected to play pivotal roles in the response to hypoxia in various tissues. HIF-1α is hydroxylated by prolylhydroxylase (PHD) in an oxygen-dependent manner, and then it is degraded in the ubiquitin proteasome system. Preceding studies have revealed that PHD inhibitors induce hypoxia-like responses. In this study, we investigated the effects of PHD inhibitors on cognitive performance in mice.
Methods: Male 5-weeks-old ddY mice were subjected to novel object recognition test for evaluation of memory performance. Dimethyloxalylglycine (DMOG) and roxadustat, PHD inhibitors, are subcutaneously injected.
Results: Subcutaneous DMOG or roxadustat 30 min before the training phase significantly lowered discrimination index. These effects were inhibited by pretreatment with YC-1, a suppressor of expression of HIF-1α. Similarly, intracerebroventricular acriflavine, an inhibitor of transcriptional activity of HIF-1α, diminished the effects of DMOG.
Conclusion: The present results suggest the possibility that an increase of HIF-1α causes cognitive impairment. Since PHD inhibitors have been used for the treatment of anemia, attention should be paid to the side effects on cognitive performance.