Parkinson's disease is a neurodegenerative disease whose hallmark pathological features include a selective loss of dopaminergic neurons in the midbrain. Ciclooxygenase-2 activity induction and oxidative stress have been implicated in the aetiology of Parkinson's disease and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson disease. Upon administration of fish oil, melatonin and vitamin E, neuroprotective effects on MPTP-induced neurotoxicity have been indicated. The aim of this study was to investigate the time course and compare the potency of these agents alone, on several parameters such as COX-2 and lipid peroxides (LPO) products associated with MPTP neurotoxicity in midbrain homogenates of C57BL/6 mice. Using fish oil (0.0368 g EPA and 0.0184 g DHA, per day), melatonin (10 mg/kg/day), and vitamin E (50 mg/Kg/day) we have now shown that COX-2 activity, LPO and nitrite/nitrate levels were significantly increased in MPTP treated mice (p < 0.001) while fish oil, melatonin and vitamin E treatment were capable of decreasing significantly the outcome of all above noted parameters (p < 0.05). The effect of fish oil on COX-2 activity and nitrite/nitrate levels was more profound than that of vitamin E or melatonin while the latter was more effective on reducing the LPO levels compared to fish oil and vitamin E. In conclusion, the outcome of the neuroprotective effects of these agents is long lasting and of variable potency indicating a different anti-inflammatory mode of action.