Sex-based differences in the prevention of stress-induced anxiety by Resolvin D5 and its precursor docosahexaenoic acid: A comparative study

Abstract

Acute stress can cause emotional dysregulation and trigger various molecular changes, including increased neuroinflammation in limbic regions. These changes have the potential to induce anxiety by disrupting brain physiology and functional connectivity. In this study, we investigated whether an 8-day treatment with inflammation-resolving compounds, specifically Resolvin D5 (RvD5) and its precursor, the omega-3 fatty acid docosahexaenoic acid (DHA), could alleviate anxiety induced by acute restraint stress (ARS) in male and female rats. Additionally, we assessed whether these effects persisted one week after treatment cessation. Serum corticosterone levels and proinflammatory cytokine levels in the hippocampus (HIP) were also assessed. Our results confirmed that ARS induced significant anxiety-like behavior in both the short and long term, with females displaying greater exploratory activity than males. Both RvD5 and DHA prevented the development of pronounced anxiety-like behavior in stressed rats, without affecting anxiety levels in non-stressed rats. Notably, the effect persisted for at least one-week post-treatment in females. The treatments also prevented the elevation of TNF alpha and interleukin-1 beta levels in the HIP and serum corticosterone levels in stressed animals. In conclusion, our findings confirm the neuroprotective profile of these compounds and indicate that the continuous use of DHA or RvD5 may have promising effects in preventing anxiety responses triggered by acute stressful event, regardless of sex. Furthermore, this study is the first to demonstrate that RvD5 can downregulate corticosterone levels in stressed animals.