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.