Irisin alleviates anxiety and deficits in fear extinction in PTSD within SPS mouse model.

Post-Traumatic Stress Disorder (PTSD), a prevalent psychological disorder, emerges subsequent to a grave traumatic incident or a succession of such events. Irisin is expressed in brain regions such as the hippocampus and prefrontal cortex and is found to have a neuroprotective function by suppressing neuroinflammation through the AMPK pathway, demonstrating its potential in treating cognitive decline, having antidepressant effects, and intervening in stress-related disorders. This study aims to explore the potential therapeutic effects of irisin on PTSD, as well as investigate the underlying mechanisms. Results showed that SPS caused anxiety-like behaviors and deficit in fear memory extinction of the mice. These SPS-induced abnormalities of the mice were reversed by exogenous irisin treatment. However, the AMPK inhibitor abolished the protective effects of irisin, indicating that irisin's therapeutic effects on SPS mice were achieved by activating AMPK. Further biochemical experiments demonstrated that irisin could increase pAMPK levels and ameliorate the overexpression of NF-κB and its downstream factors, including inflammatory factors and neurotoxic mediators, in the hippocampus, frontal cortex, and amygdala of the SPS mice. These effects of irisin were also reversed by AMPK inhibitor. Cell experiments suggest that irisin exerts anti-inflammatory effects on BV2 cells (microglia) via the AMPK/NF-κB pathway and subsequently confers anti-inflammatory benefits while enhancing cell viability in PC12 cells. The cumulative results indicate that irisin can improve behavioral deficits induced by SPS in mice by exerting anti-neuroinflammation function, and this function may be associated with the modulation of AMPK/NF-κB pathway in microglia in the brain tissues including hippocampus, cerebral cortex, and amygdala.