Stigmasterol Is Associated with Alterations in nNOS-PSD95/CAPON Signaling and Synaptic Plasticity in a PTSD Model

The efficacy of stigmasterol (STG) has not been previously evaluated in post-traumatic stress disorder (PTSD) models. Mice exposed to single prolonged stress with foot shock (SPS + FS) received oral STG (25 or 50 mg/kg) for 14 days. Serum corticosterone and serotonin levels were measured, anxiety and cognition were assessed, synaptic plasticity-related proteins and genes were quantified, and neuronal nitric oxide synthase (nNOS), nitric oxide (NO) accumulation, nNOS-postsynaptic density protein 95 (PSD95), and nNOS-carboxy-terminal PDZ ligand of nNOS (CAPON) interactions were evaluated. STG significantly reduced serum corticosterone levels and increased serotonin levels altered by SPS+FS exposure. Behavioral analyses revealed attenuation of anxiety-like behavior and cognitive deficits. STG increased hippocampal synaptic plasticity-related proteins and genes and increased the number and maturation of doublecortin⁺ cells. Additionally, STG suppressed the PTSD-induced nNOS overactivation and NO accumulation in the hippocampus and serum, and altered nNOS-PSD95 and nNOS-CAPON associations in the hippocampus. Together, these findings provide integrated in vivo evidence suggesting that STG may influence stress-related neurobiological pathways relevant to PTSD.