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

Area of Science:

• Neuroscience
• Pharmacology
• Psychiatry

Background:

• Post-traumatic stress disorder (PTSD) is a debilitating condition with limited treatment options.
• The neurobiological underpinnings of PTSD involve stress hormone dysregulation, neurotransmitter imbalances, and impaired synaptic plasticity.
• Stigmasterol (STG), a plant-derived phytosterol, has not been previously investigated for its effects on PTSD.

Purpose of the Study:

• To evaluate the efficacy of stigmasterol (STG) in an established mouse model of PTSD.
• To investigate the impact of STG on stress-related neurobiological markers, including corticosterone, serotonin, and nitric oxide pathways.
• To assess STG's effects on anxiety-like behavior, cognitive function, and synaptic plasticity in the context of PTSD.

Main Methods:

• Mice were subjected to a single prolonged stress (SPS) plus foot shock (FS) model to induce PTSD-like phenotypes.
• Oral administration of STG (25 or 50 mg/kg) was given for 14 days post-stressor exposure.
• Measurements included serum corticosterone and serotonin, behavioral tests for anxiety and cognition, hippocampal synaptic plasticity markers, and evaluation of neuronal nitric oxide synthase (nNOS) interactions.

Main Results:

• STG treatment significantly reduced elevated serum corticosterone levels and increased depleted serotonin levels in SPS+FS mice.
• Behavioral assessments showed that STG attenuated anxiety-like behaviors and improved cognitive deficits.
• STG administration upregulated hippocampal synaptic plasticity-related proteins and genes, increased neurogenesis markers (doublecortin+ cells), and normalized nNOS activity and associated protein interactions.

Conclusions:

• Stigmasterol demonstrates significant therapeutic potential for PTSD by modulating key neurobiological pathways.
• STG effectively counteracted stress-induced hormonal imbalances and neurotransmitter deficits characteristic of PTSD.
• The findings suggest STG's ability to restore synaptic function and neuroplasticity, offering a promising avenue for novel PTSD therapeutics.