Silymarin reverses post-traumatic stress-related anxiety and depression in mice by enhancing monoaminergic systems, inhibiting cytokine release, and reducing astrocytic dysfunction.

This study investigates the neuroprotective effects of silymarin, a naturally occurring flavonolignan compound, against post-traumatic stress disorder induced by single prolonged stress (SPS), which is characterized by increased anxiety and depressive-like behavior in mice. We investigated SPS-induced behavioral impairments, neurochemical depletions, and neuroimmune alterations, including astrocytic dysfunction, which are identified as key drivers of PTSD. After a triple-paradigm successive traumatic process of SPS and mice isolation for 7 days, they were treated as 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 from days 8-21. Mice were assessed for anxiety and depressive-like behaviors, followed by evaluations of neurochemical changes, adrenal weights, and measurements of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) concentrations, as well as the expression of glial fibrillary acidic protein (GFAP) in the prefrontal cortex, hippocampus, and striatum. Silymarin reduced SPS-induced anxiety-like behavior and alleviated social impairment and diminished depressive phenotype, similar to fluoxetine. Moreover, SPS-induced depletion of serotonin and dopamine concentrations, accompanied by heightened monoamine oxidase-B activity and adrenal hypertrophy, was reversed in the prefrontal cortex, hippocampus, and striatum, respectively. SPS exposure was accompanied by increased TNF-α and IL-6 in the prefrontal cortex, hippocampus, and striatum, which were reversed by silymarin. Notably, silymarin significantly reduced GFAP expression in the prefrontal cortex as well as in the hippocampal CA3 subregion. These findings demonstrate that silymarin exerts anti-PTSD-like effects through the enhancement of monoaminergic concentrations, suppression of neuroinflammation, and restoration of astrocytic function.