The neuroprotective effect of fisetin in the MPTP model of Parkinson's disease

Background: Parkinson's disease (PD) is characterized by excessive deposition of neuritic plaques known as Lewy bodies of which α-synuclein is the major contributor to neuronal death. Both oxidative stress and cytokines signaling have been proposed to play an important role in α-synuclein- induced neuronal death in MPTP and PD-related neuronal cell death. Fisetin, a natural polyphenol, possesses antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the molecular neuroprotective mechanisms of fisetin against MPTP-induced cytotoxicity are still unknown. Objective: The present study investigated the inhibitory effect of fisetin on MPTP/MPP+-induced neurotoxicity in PC12 cells. Methods: Cells were pretreated with varying concentrations of fisetin prior exposure to MPTP/MPP+. Cell viability and apoptosis were investigated using MTT assay and DNA fragmentation. The expression and release of transcription factor, pro-inflammatory cytokines, and apoptotic mediators were assessed using western blot analysis and ELISA. Results: Results showed that a pre-treatment with fisetin before exposure to MPTP/MPP+ significantly decreased MPTP/MPP+-induced cytotoxicity and cell death probably by decreasing α-synuclein expression. Mechanisms study showed that fisetin has the potential to inhibit several apoptotic and inflammatory pathways, which play important roles in the initiation and progression of PD. Conclusions: Altogether, these observations indicate that fisetin is capable of attenuating α-synuclein levels and promoting neuroprotective effects, meanwhile also present some insights into the potential signaling pathways that are involved. Thus, these findings support the role of natural polyphenols in preventive and/or complementary therapies for neurodegenerative diseases.