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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 7 days, beginning 2 days 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 7 days negated any neuroprotective effects of iNOS inhibition, suggesting that the damaging effects of inflammation last beyond 7 days in this model and the continued administration of the drug may be required.

Original publication

DOI

10.1016/j.freeradbiomed.2010.12.026

Type

Journal article

Journal

Free Radic Biol Med

Publication Date

01/03/2011

Volume

50

Pages

633 - 640

Keywords

Animals, Cytoprotection, Disease Models, Animal, Immunohistochemistry, Male, Matrix Metalloproteinase 9, Microglia, Neuroprotective Agents, Nitric Oxide Synthase Type II, Oxidopamine, Parkinson Disease, Rats, Rats, Sprague-Dawley, Sulfides, Tyrosine 3-Monooxygenase