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The aim of this study was to determine whether sesamin, a component from Acanthopanax senticosus HARMS (ASH) pharmacologically offers protection against Parkinson's disease (PD) and its related depressive behavior in rats administered rotenone. We also examined how sesamin affected the rotenone-induced loss of tyrosine hydroxylase (TH) or glial cell line-derived neurotrophic factor (GDNF)-positive neurons in the midbrain of rats. Rats were orally administered sesamin (3, 30 mg/kg) once a day for 2 weeks before an intraperitoneal injection of rotenone (2.5 mg/kg). The pole test and catalepsy test were used to evaluate the effects of sesamin administration on bradykinesia and depressive behaviors in the PD model of rats given rotenone for 5 weeks. Those effects were compared with the ASH administrated group (250 mg/kg). Treatment with sesamin for seven weeks resulted in prophylactic effects on rotenone-induced parkinsonian bradykinesia and catalepsy, and the effects were equivalent to ASH effects. Immunohistochemistical analysis using TH or GDNF antibody showed that sesamin provided cytoprotective effects against rotenone-induced loss of DA cells. The results suggest that it may be possible to use the ASH and sesamin for the prevention of nigral degenerative disorders, e.g., PD with depression, caused by exposure to pesticide or environmental neurotoxins in general.