OBJECTIVES: To investigate the effect of orally administered cytidine-5'-diphosphocholine (citicholine) (50,100,200 mg/kg), α-tocopherol (Vit E; 25 mg/kg), caffeine (10 mg/kg), L-dopa (25 mg/kg) or the combination of Vit E, caffeine with citicholine (100 mg/kg) on nigrostriatal neuronal damage induced in the mice brain by subcutaneous (s.c.) rotenone. METHODS: Swiss male mice received rotenone (1.5 mg/kg, s.c, three times per week) alone or with other drugs for 2 weeks. Mice were evaluated for brain malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO), paraoxonase-1 (PON-1), acetylcholinesterase (ACHE), interlukin-1beta (IL-1β), nuclear factor kappa B (NF-κB) and monocyte chemoattractant protein (MCP-1). Histopathologic examination was also done. RESULTS: Cticholine co-treatment at 50, 100 or 200 mg/kg significantly decreased brain MDA and increased PON-1 activity in a dose-dependent manner. When given at 200 mg/kg, it also significantly decreased NO production, while at 100 and 200 mg/kg significantly increased GSH brain. MCP-1 significantly decreased upon treatment with 100 or 200 mg/kg of citicholine. IL-1 β and NF-κB significantly decreased and AChE significantly increased by 200 mg/kg citicholine. Oxidative stress and inflammatory biomarkers also showed favorable changes after Vit E, caffeine or L-dopa. However, the combination of Vit E and/or caffeine with 100 mg/kg citicholine was not superior to that of only citicholine at 100 or 200 mg/kg. CONCLUSIONS: Citicholine is neuroprotective in acute rotenone nigrostriatal degeneration via antioxidant and anti-inflammatory properties. It is suggested that citicholine may have a role in treatment of Parkinson's disease by decreasing neuro-inflammation and oxidative stress, preventing the development of neuronal damage.