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. 2004 May 17;1(1):6.
doi: 10.1186/1742-2094-1-6.

Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease

Rosario Sánchez-Pernaute  1 , Andrew Ferree, Oliver Cooper, Meixiang Yu, Anna-Liisa Brownell, Ole Isacson
Affiliations

Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease

Rosario Sánchez-Pernaute et al. J Neuroinflammation. .

Abstract

Several lines of evidence point to a significant role of neuroinflammation in Parkinson's disease (PD) and other neurodegenerative disorders. In the present study we examined the protective effect of celecoxib, a selective inhibitor of the inducible form of cyclooxygenase (COX-2), on dopamine (DA) cell loss in a rat model of PD. We used the intrastriatal administration of 6-hydroxydopamine (6-OHDA) that induces a retrograde neuronal damage and death, which progresses over weeks. Animals were randomized to receive celecoxib (20 mg/kg/day) or vehicle starting 1 hour before the intrastriatal administration of 6-OHDA. Evaluation was performed in vivo using micro PET and selective radiotracers for DA terminals and microglia. Post mortem analysis included stereological quantification of tyrosine hydroxylase, astrocytes and microglia. 12 days after the 6-OHDA lesion there were no differences in DA cell or fiber loss between groups, although the microglial cell density and activation was markedly reduced in animals receiving celecoxib (p < 0.01). COX-2 inhibition did not reduce the typical astroglial response in the striatum at any stage. Between 12 and 21 days, there was a significant progression of DA cell loss in the vehicle group (from 40 to 65%) that was prevented by celecoxib. Therefore, inhibition of COX-2 by celecoxib appears to be able, either directly or through inhibition of microglia activation to prevent or slow down DA cell degeneration.

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Figures

Figure 1
Figure 1
A) Using micro-PET and selective radioactive tracers we measured in vivo the extent of dopamine terminal loss and inflammatory response 12 (top panel) and 21 (bottom panel) days after the 6-OHDA lesion. Color-coded images of 11C-CFT ((2β-carbomethoxy-3β-(4-fluorophenyl) tropane, a dopamine transporter ligand) and 11C-PK11195 (a peripheral-type benzodiazepine ligand that binds to microglia) in a representative animal of each group. As reported in our previous study [28] 6-OHDA injection resulted in a marked decrease of 11C-CFT binding in the striatum and a parallel increase in 11C PK-11195 binding in the control (vehicle) group. The increase in 11C PK 11195 binding was absent in COXIB treated animals and in both groups at 21 days post lesion. B-C) Microphotographs of TH fiber density in the striatum in representative animals (same as shown in A). D) Volumetric analysis of fiber loss in the lesioned striatum showed a marked reduction at 12 days, that partially recovered at 21 days post-lesion (*, p < 0.01). TH striatal volumes were significantly larger in COXIB treated than in the vehicle group (#, p < 0.01). E) At 12 days post-lesion, both treatment groups displayed a ~40% loss of TH positive cell bodies in the SN. The progressive loss of DA cell bodies between 12 and 21 days post-lesion in the vehicle treated rats was significant (* p< 0.01) while there was no significant difference in DA cell bodies in the COXIB treated rats between 12 and 21 days. At 21 days the DA cell loss in the SN was significantly higher in vehicle treated animals (#, p < 0.05). Scale bar: 30 μm.
Figure 2
Figure 2
The microglial response to 6-OHDA injection was significantly attenuated in the striatum of COXIB treated animals. Photomicrographs of activated microglia immunohistochemistry in a representative striatal section of a vehicle (A, B) and a COXIB (C, D) treated animal 12 days after the injection of 6-OHDA. All images are ipsilateral to the injection side. E, F) Bar graphs showing the stereological quantification of activated microglia cell density at 12 (E) and 21 days (F). Microglial density was significantly reduced in the striatum of COXIB treated rats (treatment effect p < 0.05) both in the lesioned and in the contralateral striata. However, the microglia response was not completely abolished in COXIB treated animals, as microglia density was significantly higher in the 6-OHDA injected striatum (p < 0.01) and the density was higher in the lesioned/treated striatum than in the contralateral/untreated striatum (p < 0.05). Scale bar: 100 μm for A and C and 25 μm for B and D.
Figure 3
Figure 3
Microglial density in the ventral midbrain. Photomicrographs of activated microglia immunohistochemistry in a representative midbrain section of a vehicle (A, B) and a COXIB (C, D) treated animal 21 days after the injection of 6-OHDA. E, F) Bar graphs showing the stereological quantification of activated microglia cell density at 12 (E) and 21 days (F). Microglial density was significantly reduced in the ventral midbrain of COXIB treated rats (treatment effect F= 6.28, p < 0.05) both in the lesioned and in the contralateral striata. Microglial density was higher at 21 days in all groups and was significantly higher in the vehicle group ipsilateral to the lesion (p < 0.05). Scale bar: 25 μm.
Figure 4
Figure 4
Astroglial response in the striatum. Photomicrographs of representative sections of the ipsilateral (A, B) and contralateral (C, D) striatum of an animal receiving COXIB at 21 days. E, F) Bar graphs showing the GFAP positive density in the striatum. E) Astroglial density was significantly higher in the lesioned striatum (P < 0.01), with no significant differences between treatment groups. F). Scale bar: 25 μm.
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