1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) does not elicit long-lasting increases in cyclooxygenase-2 expression in dopaminergic neurons of monkeys.

To elucidate the role of the prostaglandin synthase cyclooxygenase-2 (Cox-2) and the mechanisms of dopaminergic (DA) neurodegeneration, monkeys were injected subacutely or chronically (n = 5/group) with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Chronically treated animals developed parkinsonian signs and were killed 6 months after the last treatment; tyrosine hydroxylase-expressing neurons decreased in all substantia nigra (SN) cell groups in both treatment groups. In untreated controls (n = 3), there was low Cox-2 expression in ventral SN DA neurons and high expression in ventral tegmental area neurons. In subacutely treated monkeys, Cox-2 expression increased in surviving DA cells, particularly in the ventrolateral SN. In chronically treated monkeys, enhanced Cox-2 expression appeared only in surviving ventral tegmental area and ventral SN neurons. Thus increased Cox-2 did not persist in other SN neurons after discontinuing 1-methyl-4-phenyl-1,2,36-tetrahydropyridine. Some DA neurons in treated but not control monkeys expressed the active nuclear form of phospho-c-Jun, but not the active form of nuclear factor-kappaB. We conclude that Cox-2 expression does not confer vulnerability to neurodegeneration in DA neurons and that it is unlikely that a subacute insult to DA neurons can perpetuate degeneration through Cox-2 activation. Other mechanisms, probably through the Jun N-terminal kinase cascade, lead to DA cell death in this model.