Silymarin reverses post-traumatic stress-induced memory impairment in mice by containment of oxidative stress, cholinergic dysfunction, and modulation of neuronal caspase-3 expression.

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition marked by cognitive deficits and neurobiological disturbances, including oxidative stress, neuroinflammation, cholinergic dysfunction, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and apoptosis. This study investigated the protective effects of silymarin against single prolonged stress (SPS)-induced PTSD-like changes in mice. Mice were exposed to a triple stress model consisting of restraint stress, forced swim test and brief ether-induced loss of consciousness, and left singly for 7 days of isolation. Animals were assigned to control (saline 10 mL/kg, p.o), SPS, SPS + silymarin (25, 50, 100 mg/kg, p.o), and SPS + fluoxetine (10 mg/kg, p.o) groups for 21 days. Behavioral performance was assessed using the novel object recognition, Y-maze, and open field tests. We quantified serum corticosterone concentration. Oxidative stress and immune markers, viz malondialdehyde, nitrite, reduced glutathione, superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), myeloperoxidase (MPO), and acetylcholinesterase (AChE) were assayed in the prefrontal cortex, hippocampus and striatum. Neuronal cell death and caspase-3 expression were evaluated using hematoxylin and eosin staining and immunohistochemistry. SPS exposure impaired recognition, working memory, and reduced locomotor activity, which were reversed by silymarin. Silymarin reduced SPS-induced increased malondialdehyde and nitrite levels, accompanied by increased glutathione, GST, SOD and catalase levels in the prefrontal cortex, hippocampus and striatum, respectively. Silymarin treatment attenuated MPO and AChE activities in the prefrontal cortex, hippocampus and striatum. Silymarin modulated caspase-3 expression in a brain-region-dependent manner, notably inhibiting it in the dentate gyrus of the hippocampus, increasing it in the prefrontal cortex, and preserving neuronal cytoarchitecture in all regions. These findings suggest that silymarin provides broad neuroprotection in SPS-induced PTSD through apoptosis modulation, enhancing antioxidants and anti-inflammatories, with upregulated cortical cholinergic transmissions and inhibition of corticosterone release.