Inhibition of phosphodiesterase-4 by rolipram alleviates anxiety-like behavior in mice with PTSD by modulating neuroinflammation and synaptic plasticity via cAMP signaling.

BACKGROUND

Post-traumatic stress disorder (PTSD) is a mental disorder in which individuals exhibit fear and anxiety due to recurrent painful memories. Rolipram, a PDE4 inhibitor, exerts neuroprotective effects via anti-neuroinflammation, yet the role of PDE4 in PTSD pathogenesis remains unclear. This was addressed by exploring the molecular mechanisms through which rolipram exerts its therapeutic effects in PTSD.

METHODS

The PTSD mouse model was established by a combined protocol of single prolonged stress and footshock (SPS&FS). The activity of PDE4 in the brain was measured using high-performance liquid chromatography (HPLC). The behavioral effects of rolipram (1 mg/kg/d for 14 d) on the PTSD model were assessed by behavioral tests. Additionally, the impact of rolipram on neuroinflammation and synaptic deficits was evaluated in these mice using a combination of biochemical assays and morphological analyses.

RESULTS

The PTSD mice showed abnormal behavioral changes, increased PDE4 activity, elevated levels of inflammation, and synaptic deficits. Administration of rolipram (1 mg/kg/d, i.p.) restored cAMP/PKA signaling, reduced the release of pro-inflammatory cytokines (IL-6 and IL-1β) and inhibited microglial activation in PTSD mice. Additionally, rolipram ameliorated PTSD-like behaviors and synaptic defects. The neuroprotective and anti-inflammatory effects of rolipram were abolished by co-treatment with the PKA inhibitor H89.

CONCLUSION

In summary, we demonstrated that rolipram ameliorated PTSD-like behavioral abnormalities, neuroinflammatory responses, and hippocampal synaptic deficits by activating the cAMP-PKA signaling pathway. These results suggest that PDE4 inhibition may serve as a promising therapeutic strategy for PTSD.