Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration - PubMed (original) (raw)

Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

Peter Teismann et al. Proc Natl Acad Sci U S A. 2003.

Abstract

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 E(2) have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E(2) synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice. COX-2 induction occurs through a JNKc-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.

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Figures

Figure 1

Figure 1

Ventral midbrain COX-1 and COX-2 mRNA and protein expression after MPTP. COX-2 mRNA levels are increased by 4 days after MPTP injection (A) compared with controls (C), and almost return to basal levels by 7 days. COX-2 protein contents are minimal in saline-injected mice (sal) (D) but rise in a time-dependent manner after MPTP injection (F). COX-1 expression is not altered by MPTP (A, B, D, and E). Ventral midbrain PGE2 levels are also increased 4 days after MPTP (G). Data are mean ± SEM for four to six mice per group. *, P < 0.05, compared with saline (Newman–Keuls post hoc test).

Figure 2

Figure 2

Ventral midbrain illustration of COX-2 immunolocalization. No COX-2-positive cells are seen in saline-injected mice (A and enlarged Inset from A in B). Conversely, COX-2-positive cells are abundant after MPTP (C and enlarged Inset from C in D, arrow). Double immunofluorescence confirms that COX-2 (green) is highly expressed in TH-positive neurons (red; E–G) and not in MAC-1-positive cells (H-J; red) or GFAP-positive cells (K–M; red). [Scale bars, 250 μm (A and C), 10 μm (B and D–G), and 20 μm (H–M).]

Figure 3

Figure 3

Ventral midbrain COX-2 expression is minimal in normal human specimens but is increased 3-fold in PD samples (A). Ventral midbrain PGE2 levels are also increased in PD (B). COX-2 (blue) is not detected in neuromelanized (brown) dopaminergic neurons in controls (C and D) but is well detected in PD (E–G). COX-2 immunostaining (F; arrow) is visible in cells with neuromelanin (F; arrowhead). COX-2 immunostaining is found in the core of a Lewy body (G; arrowhead). Data are mean ± SEM for 3–6 samples for COX-2 protein and 11 samples for PGE2 assessment. *, P < 0.05, compared with normal controls (Newman–Keuls posthoc test). (Scale bar, 25 μm.)

Figure 4

Figure 4

Effect of COX-2 ablation and JNK pathway inhibition on MPTP-induced neuronal loss. TH-positive neuronal counts are shown in Table 1 and appear comparable between saline-injected _Ptgs2_−/− and Ptgs2+/+ mice (A and B and Table 1). SNpc TH-positive neurons are more resistant to MPTP in _Ptgs2_−/− (D) than in Ptgs2+/+ (C) mice, 7 days after MPTP injection. CEP-11004 protects Ptgs2+/+ mice against MPTP neurotoxicity (E). Treatment of _Ptgs2_−/− mice with CEP-11004 does not enhance protection against MPTP (F and Table 1). (G) Ventral midbrain MPTP-induced c-Jun phosphorylation (ρ-c-Jun) inhibition by 1 mg/kg CEP-11004. (H) Ventral midbrain MPTP-induced COX-2 up-regulation is also inhibited by 1 mg/kg CEP-11004. Data are mean ± SEM for three to six mice per group. *, P < 0.05, compared with the other three groups (Newman–Keuls posthoc test). (Scale bar, 250 μm.)

Figure 5

Figure 5

TH-positive neurons and striatal fibers are more resistant to MPTP in mice treated with rofecoxib (25 or 50 mg/kg p.o.; D and F) than in mice receiving vehicle (B), 7 days after MPTP injection (SNpc neuronal counts are shown in G and striatal fiber optical density is shown in H). Rofecoxib by itself has no effect on TH-positive neurons (A, C, and E). Data are mean ± SEM for three to six mice per group. *, P < 0.05, compared with saline-treated controls; #, P < 0.05, compared with rofecoxib-treated MPTP animals (Newman–Keuls posthoc test). (Scale bar, 250 μm.)

Figure 6

Figure 6

Expression of inflammatory and oxidative stress markers after MPTP. Two days after MPTP injection, mRNA expression of MAC-1 (A and B), ICE (A and C), gp91 (A and D), and iNOS (A and E) are increased in the ventral midbrain and none is attenuated by COX-2 ablation. MAC-1 immunoreactivity is minimal in saline-injected mice in ventral midbrain (F), but is increased after MPTP injection (G; Inset shows MPTP-induced microglial activation at higher magnification). (H) COX-2 inhibition does not attenuate MPTP-induced microglial activation. (I) MPTP increases ventral midbrain protein-bound cysteinyl-dopamine, which is blocked by rofecoxib. Data are mean ± SEM for four to six mice per group. *, P < 0.05, compared with saline treated groups; #, P < 0.05, compared with the other five groups (Newman–Keuls posthoc test). (Scale bar, 250 μm.)

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