Silibinin ameliorates depression/anxiety-like behaviors of Parkinson's disease mouse model and is associated with attenuated STING-IRF3-IFN-β pathway activation and neuroinflammation

Depression and anxiety are common neuropsychiatric symptom of Parkinson's disease (PD), reflecting reduced quality of life in patients with PD. Silibinin (silybin), a flavonoid extracted and isolated from the fruit of Silybum marianum (L.) Gaertn, is widely used for the treatment of hepatic diseases. We report here that silibinin shows anti-depressant and anti-anxiety effects on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model mice with PD. All the results of open field test, elevated plus maze test, tail suspension test and forced swimming test demonstrated that silibinin administration significantly attenuated MPTP-induced depression/anxiety. Hematoxylin-eosin (HE) staining and Nissl staining results showed that MPTP injection caused the damage of hippocampal neurons, but this was ameliorated by oral administration of silibinin. Silibinin significantly restored hippocampal levels of 5-hydroxyptramine (5-HT) and noradrenaline (NA), two important neurotransmitters for regulating mood, which decreased in MPTP-injected mice. Neuroinflammation, as reflected by the increased expressions of IL-1β, TNFα and IFN-β, was marked in the hippocampus of MPTP-treated mice, accompanying increased stimulator of interferon genes (STING) and interferon regulatory factor-3 (IRF3). Silibinin administration, however, down-regulated the levels of IL-1β, TNFα and IFN-β, as well as STING and IRF3, protecting MPTP-induced PD model mice. These findings indicate that silibinin has a potential of being further developed as a therapeutic for depression and anxiety in PD.