PERK inhibitor (ISRIB) improves depression-like behavior by inhibitions of HPA-axis over-activation in mice exposed to chronic restraint stress
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View abstract on PubMed
Summary
This summary is machine-generated.Blocking the PERK pathway with ISRIB alleviated depression-like behaviors in male mice exposed to chronic stress. This suggests PERK inhibitors may offer a therapeutic strategy for mood disorders by targeting stress-induced neuropathology.
Area Of Science
- Neuroscience
- Molecular Biology
- Psychiatry
Background
- Stressful life events are strongly linked to depression.
- The role of protein kinase R (PKR)-like ER kinase (PERK) in inflammation-related depression is known, but its involvement in chronic stress-induced depression is unclear.
- Understanding the mechanisms of chronic stress on the brain is crucial for developing effective depression treatments.
Purpose Of The Study
- To investigate whether blocking the PERK pathway can alleviate depression-like behaviors in animals subjected to chronic restraint stress (CRS).
- To explore the underlying mechanisms by which PERK inhibition affects CRS-induced neuropathology.
- To determine the potential of PERK pathway inhibitors as a therapeutic strategy for depression.
Main Methods
- Mice were exposed to chronic restraint stress (CRS).
- Administration of ISRIB (a PERK pathway inhibitor) for two weeks.
- Assessment of depression-like behaviors using sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST).
- Measurement of serum corticosterone levels, hippocampal glucocorticoid receptor (GR) expression, and FosB expression in the hypothalamic paraventricular nucleus (PVN).
- Evaluation of hippocampal neurogenesis.
Main Results
- CRS induced depression-like behaviors in mice, including anhedonia and increased immobility.
- ISRIB administration significantly improved depression-like behaviors in male mice exposed to CRS.
- In female mice, ISRIB improved anhedonia but not other depression-like behaviors.
- ISRIB reversed hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, reducing corticosterone levels.
- ISRIB preserved hippocampal neurogenesis and normalized GR and FosB expression in relevant brain regions.
Conclusions
- Blocking the PERK pathway with ISRIB effectively alleviates depression-like behaviors and HPA axis hyperactivity in male mice subjected to chronic stress.
- The findings suggest that ER stress plays a significant role in the neuropathology of chronic stress-induced depression.
- PERK pathway inhibitors represent a promising therapeutic avenue for mood disorders, particularly those linked to chronic stress.
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