Potential antidepressant-like effects of N-3 polyunsaturated fatty acids through inhibition of endoplasmic reticulum stress

Abstract

Rationale: The growing evidence has demonstrated the importance of endoplasmic reticulum stress (ERS) in the pathophysiology of depression. ERS genes were considered to be potential novel therapeutic targets for depression.

Objectives: To clarify the mechanisms of the chronic unpredictable mild stress (CUMS)-induced ERS response and the potential contributing pathways in depression, and further investigate the potential link between N-3 polyunsaturated fatty acids (PUFAs) and stress-induced ERS disturbances.

Methods: This study analyzed the expression of ERS-related genes including GRP78, ATF-4, ATF-6, XBP-1, and CHOP, and sigma-1R with real-time PCR in peripheral blood mononuclear cell (PBMC) RNA samples from participants. All of the rats except for those in the control groups were subjected to 5 consecutive weeks of CUMS to establish the depression model, and the antidepressant effects of N-3 PUFAs were observed by behavior tests. Moreover, the effect of diet and stress on the ERS pathways was also investigated using the western blot.

Results: Blood CHOP, ATF-4, and XBP-1 levels were notably elevated in depressed patients relative to healthy individuals. Moreover, increased sigma-1R and decreased ATF-6 implied the protective role of sigma-1R through modulating ERS in patients with depression. Animal studies disclosed the novel findings that supplementary N-3 PUFAs in rats alleviated CUMS-induced disturbance of ERS through the ATF-4/XBP-1/CHOP pathway, implying its potential strategy for depression.

Conclusion: CUMS-induced depressive-like behaviors are related to the disturbance of ERS. Furthermore, supplementary N-3 PUFAs might be an effective way to alleviate ERS.

Keywords: Depression; Endoplasmic reticulum stress; N-3 PUFAs; Sigma-1 receptor.