COX-2 Activity is Required for Nigral Degeneration

Subject: COX-2 Activity is Required for Nigral Degeneration

Date: 5/6/2003

Cylooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration
P Teismann, K Tieu, DK Choi, DC Wu, A Naini, S Hunot, M Vila, V Jackson-Lewis, S Przedborski
PNAS 2003;100:5473-5478

Activity of the COX-2 enzyme is required for MPTP-induced nigral degeneration, according to this study. COX-2 is an inducible form of cyclooxygenase. It is the form mainly responsible for production of pro-inflammatory prostaglandins during pathological events, although this study provides evidence that inflammation is not the pathway through which COX-2 exerts its effects in this model.

MPTP was administered to mice with and without the gene for COX-2 production. Results showed:
--COX-2, but not COX-1, is upregulated following MPTP administration, by approximately 2-3 fold. Enzymatic activity is also increased.

--Upregulation was primarily confined to dopaminergic neurons, and not glia or astrocytes.

--COX-2 knockout mice were largely protected from MPTP toxicity, an effect that could be mimicked in normal mice by administration of the COX-2 inhibitor rofecoxib (Vioxx), indicating the pathogenic effect of COX-2 is likely due to enzymatic activity rather than nonenzymatic effects.

--The pathogenic effect of COX-2 activity could be mitigated by an inhibitor of JNK, a central signal-pathway enzyme acting downstream from COX-2.

--Absence or inhibition of COX-2 did not interfere with MPTP metabolism, nor MPTP-induced microglial activation, indicating that anti-inflammatory action does not play a role in the protection provided by COX-2 inhibition.

--COX-2-inhibited mice had lower levels of the dopamine oxidation product dopamine quinone.

--COX-2 was upregulated in human PD brain compared to controls, and was largely confined to nigral neurons.

The authors state, “Collectively, our data provide evidence for COX-2 upregulation in MPTP and PD and support a significant role in both the mechanism and the specificity of MPTP- and PD-induced [nigral] dopaminergic cell death.”