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Paeonol is a major phenolic compound of the Chinese herb Cortex Moutan and is known for its antioxidant, anti-inflammatory, and antitumor properties.The present study was designed to explore the neuroprotective potential and mechanisms of paeonol on a1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse model of Parkinsons disease (PD).MPTP (25 mg/kg), followed by probenecid (250 mg/kg), were administered intraperitoneally for five consecutive days to induce the mouse model of PD.Then,paeonol (20 mg/kg) was administrated orally for 21 days.Behavior was assessed using the rotarod and open-field tests.Additionally, the amount of tyrosine hydroxylase (TH), microglia,and interleukin-1β (IL-1β) in the substantia nigra pars compacta (SNpc) were evaluated by immunohistochemical staining.We found that the MPTP/p-induced motor deficits were significantly improved after long-term treatment with paeonol.Paeonol treatment decreased the MPTP/p-induced oxidative stress, as determined by evaluating the activity levels of superoxide dismutase, catalase, and glutathione.Additionally, MPTP/p-induced neuroinflammation was assessed by examining the amounts of microglia and IL-1β, which were significantly decreased after paeonol treatment.Paeonol treatment improved the MPTP/p-induced dopaminergic neurodegeneration, as measured by observing the TH level in the SNpc.In conclusion, paeonol exerted neuroprotective effects on the MPTP/p-induced mouse model of PD, possibly by decreasing the amount of damage from oxidative stress and neuroinflammation on dopaminergic neurons.Collectively, the results demonstrate that paeonol has the potential to serve as a novel treatment for PD.