Neuroprotection by the selective iNOS inhibitor GW274150 in a model of Parkinson disease

Neuroinflammation and the activation of inducible nitric oxide synthase (iNOS) have been proposed to play a role in the pathogenesis of Parkinson disease (PD). In this study we investigated the effects of the selective iNOS inhibitor GW274150 in the 6-OHDA model of PD. 6-OHDA administration was asso...

Full description

Saved in:
Bibliographic Details
Published in:Free radical biology & medicine 2011-03, Vol.50 (5), p.633-640
Main Authors: Broom, Lauren, Marinova-Mutafchieva, Lilia, Sadeghian, Mona, Davis, John B., Medhurst, Andrew D., Dexter, David T.
Format: Article
Language:English
Subjects:
6-OHDA
Animals
antigens
Cytoprotection
Disease Models, Animal
dopamine
drugs
Free radicals
gelatinase B
high performance liquid chromatography
immunocytochemistry
Immunohistochemistry
inducible nitric oxide synthase
inflammation
iNOS
Male
Matrix metalloproteinaise-9
Matrix Metalloproteinase 9 - analysis
Microglia
Microglia - drug effects
Microglia - enzymology
Microglia - pathology
neuroglia
Neuroinflammation
Neuroprotection
Neuroprotective Agents - administration & dosage
neuroprotective effect
nitric oxide
Nitric Oxide Synthase Type II - antagonists & inhibitors
Oxidopamine - metabolism
Parkinson disease
Parkinson Disease - enzymology
Parkinson Disease - pathology
pathogenesis
Rats
Rats, Sprague-Dawley
Sulfides - administration & dosage
Tyrosine 3-Monooxygenase - analysis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Neuroinflammation and the activation of inducible nitric oxide synthase (iNOS) have been proposed to play a role in the pathogenesis of Parkinson disease (PD). In this study we investigated the effects of the selective iNOS inhibitor GW274150 in the 6-OHDA model of PD. 6-OHDA administration was associated with increased numbers of cells expressing iNOS. Administration of the iNOS inhibitor twice daily for 7days, beginning 2days after the 6-OHDA lesioning, led to a significant neuroprotection as shown by assessment of the integrity of the nigrostriatal system by tyrosine hydroxylase immunocytochemistry and HPLC assessment of striatal dopamine content. However, GW274150 displayed a bell-shaped neuroprotective profile, being ineffective at high doses. 6-OHDA lesioning was associated with an increase in microglial activation as assessed by the MHC II antigen OX-6 and the number of matrix metalloproteinase 9 (MMP-9)-immunopositive cells. NO is a known modulator of MMP-9, and iNOS inhibition was associated with decreased numbers of MMP-9-immunopositive cells, culminating in a reduction in the numbers of reactive microglia. Withdrawal of GW274150 for a further 7days negated any neuroprotective effects of iNOS inhibition, suggesting that the damaging effects of inflammation last beyond 7days in this model and the continued administration of the drug may be required.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2010.12.026