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.
Vázquez-Claverie
Marianne
M
Laboratory of Regenerative Therapy, Department of Neurology and Neuroscience Division, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
Garrido-Gil
Pablo
P
San Sebastián
Waldy
W
Belzunegui
Silvia
S
Izal-Azcárate
Amaya
A
López
Berta
B
Marcilla
Irene
I
Luquin
María Rosario
MR
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000473:pathology
D016328:NF-kappa B; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; D004298:Dopamine