title: Neuroprotection by the selective iNOS inhibitor GW274150 in a model of Parkinson disease.
abstract: 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.
authors.affiliation: Parkinson's Disease Research Group, Centre for Neuroscience, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Broom
authors.forename: Lilia
authors.initials: L
authors.lastname: Marinova-Mutafchieva
authors.forename: Mona
authors.initials: M
authors.lastname: Sadeghian
authors.forename: John B
authors.initials: JB
authors.lastname: Davis
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
mesh_terms: D000818:Animals; D019610:Cytoprotection; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D016627:Oxidopamine / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000008:administration & dosage*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: D018696:Neuroprotective Agents; D013440:Sulfides; C409004:GW 274150; D016627:Oxidopamine; D052247:Nitric Oxide Synthase Type II; D014446:Tyrosine 3-Monooxygenase; D020780:Matrix Metalloproteinase 9