Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease

To study the possible role of the isoenzymes of cyclooxygenase COX‐1 and COX‐2 in the MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) mouse model of Parkinson's disease we used acetylsalicylic acid, a COX‐1/COX‐2 inhibitor, in comparison with meloxicam, a preferential COX‐2 inhibitor. As markers of protection we determined the effects on MPTP‐induced striatal dopamine depletion, locomotor activity, cell loss, and tyrosine hydroxylase immunoreactivity (TH‐IR) in the substantia nigra pars compacta. Male C57BL/6 mice (n = 82) were treated with a single dose of acetylsalicylic acid (10, 50, 100 mg/kg i.p.) or meloxicam (2, 7.5, 50 mg/kg i.p.) immediately prior to administration of MPTP (30 mg/kg s.c.) or saline. After 7 days the mice were sacrificed to analyze striatal dopamine and metabolite levels. Nigral sections were processed for Nissl‐staining and TH‐IR. In the saline‐treated MPTP control group striatal dopamine levels were reduced to 15.9% of control values. Dopamine depletion was significantly attenuated to values of 37.1 and 38.6% of saline control values by acetylsalicylic acid (50 and 100 mg/kg) and to values of 36 and 40% by meloxicam (7.5 and 50 mg/kg), respectively. MPTP‐induced decrease of locomotor activity was significantly attenuated by acetylsalicylic acid and meloxicam. Remarkably, the MPTP‐induced decrease of TH‐IR as well as the loss of nigral neurons was nearly completely prevented by acetylsalicylic acid (100 mg/kg) and meloxicam (7.5 and 50 mg/kg). In conclusion, the inhibition of either COX‐1/COX‐2 by acetylsalicylic acid or preferentially COX‐2 by meloxicam provided a clear neuroprotection against MPTP‐toxicity on the striatal and nigral levels. Synapse 39:167–174, 2001. © 2001 Wiley‐Liss, Inc.