Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

P Teismann, K Tieu, DK Choi, DC Wu… - Proceedings of the …, 2003 - National Acad Sciences
P Teismann, K Tieu, DK Choi, DC Wu, A Naini, S Hunot, M Vila, V Jackson-Lewis…
Proceedings of the National Academy of Sciences, 2003National Acad Sciences
Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis
characterized by the loss of the nigrostriatal dopaminergic neurons, which can be modeled
by the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Increased
expression of cyclooxygenase type 2 (COX-2) and production of prostaglandin E2 have
been implicated in neurodegeneration in several pathological settings. Here we show that
COX-2, the rate-limiting enzyme in prostaglandin E2 synthesis, is up-regulated in brain …
Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of the nigrostriatal dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Increased expression of cyclooxygenase type 2 (COX-2) and production of prostaglandin E2 have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E2 synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice. COX-2 induction occurs through a JNK/c-Jun-dependent mechanism after MPTP administration. We demonstrate that targeting COX-2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, we provide evidence that COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone, which has been implicated in the pathogenesis of PD. This study supports a critical role for COX-2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX-2 inhibitors, and their ability to penetrate the blood–brain barrier, these drugs may be therapies for PD.
National Acad Sciences