Antidepressant-like action of hypoxic postconditioning is accompanied by the up-regulation of hippocampal HIF-1α and erythropoietin

Abstract

Objective. The aim of the study was to reveal the role of HIF-1 in the effects of hypoxic postconditioning in the rat experimental model of depression learned helplessness.
 Materials and methods. The studies were performed in the learned helplessness paradigm which represents a reliable experimental model of depression in rats. The development of the pathology was evaluated in the behavioral open field test and by the baseline level of plasma corticosterone. Correction of behavioral deficit was performed by three episodes of hypoxic postconditioning (360 mmHg, 2 h). Changes in the immunopositivity of HIF-1 and erythropoietin in the hippocampus of rats were evaluated. An inhibitor of HIF-1 subunit translation topotecan (1 mg/kg, i.p., Santa Cruz, USA) was used on the 4th day after the footshock stress. On the 9th day, animals were tested in the open field test to assess the level of depressive-like behavior.
 Results. It was shown that postconditioning by three episodes of mild hypobaric hypoxia resulted in the correction of behavioral deficit produced by the learned helplessness aversive stress, and the levels of corticosterone did not differ from the baseline in these animals. These behavioral and hormonal effects were accompanied by the increased level of immunopositive HIF-1 and its transcriptional downstream target erythropoietin in the dorsal and ventral hippocampus. Using of HIF-1 inhibitor topotecan dramatically worsen the severity of the depressive-like symptoms.
 Conclusion. The findings suggest that HIF-1 appears to have the antidepressant-like activities and that hypoxic postconditioning-induced stimulation of HIF-1 and erythropoietin level might contribute to the endogenous mechanisms which compensate for the pathogenic effects of stressors, particularly for the development of stress-induced depression.