Objective: To investigate the effect of the prostaglandin El analogue misoprostol on oxidative stress and neurodegeration caused by subcutaneous rotenone administration in rats. Methods: Rotenone was administered in a dose of 1.5 mg/kg every other day for 2 weeks. Starting from the 1 st day of rotenone injection, rats were subcutaneously treated with misoprostol at doses of 10,100 or 1 000 μ g/kg. Rats were evaluated for brain lipid peroxidation (malondialdehyde: MDA), reduced glutathione (GSH),nitric oxide (NO) levels, and paraoxonase-1 (PON-1) activity. The concentrations of the anti-apoptotic protein B cell/lymphoma-2 (Bcl-2) were determined in the striatum. Histopathologic examination and the expression of inducible nitric oxide synthase (iNOS) in the cerebral cortex and striatum were also performed. Results: Compared with the vehicle-treated group, rotenone caused a significant increase in brain lipid proxidation (MDA) by 61％ (P＜0.05) accompanied by an increase in NO by 73.1％ (P＜0.05) and a decrease in GSH concentration by 29.4％ (P＜0.05). In addition, brain PON-1 activity significantly decreased by 63.0％ (P＜0.05) and striatal Bcl-2 significantly decreased by 27.9％ (P＜0.05) with respect to the corresponding control value. Brain sections from rotenone treated rats showed extensive dark pyknotic and apoptotic nuclei in neurons, shrunken cytoplasm and peri neuronal vacuolation. Rotenone also caused pronounced expression of iNOS in the cerebral cortex and striatum. Treatment with misoprostol at doses of 100 and 1 000 μ g/kg resulted in decreased brain MDA (by 16.5％-23.0％) (P＜0.05) and NO levels (by 37.1％-40.7％) (P＜0.05) and increased GSH concentrations (by 18.8％-30.1％) (P＜0.05). PON-1 activity was significantly increased by 80.0％-1 14.8％ (P＜0.05) by misoprostol at 100 and 1 000 μig/kg, respectively. In addition, misoprostol treatment restored striatal Bcl-2 concenlrations to its normal value. Misoprostol treatment resulted in markedly reduced brain injury and decreased iNOS expression in the cerebral cortex and striatum of rotenone intoxicated rats. Conclusions: These data suggest that misoprostol prevents the rotenone-induced neurodegeneration in rat brain by reducing brain oxidative stress.