title: An angiogenic inhibitor, cyclic RGDfV, attenuates MPTP-induced dopamine neuron toxicity.
abstract: We previously demonstrated that several dopamine (DA) neurotoxins produced punctate areas of FITC-labeled albumin (FITC-LA) leakage in the substantia nigra and striatum suggesting blood brain barrier (BBB) dysfunction. Further, this leakage was co-localized with αvβ3 integrin up-regulation, a marker for angiogenesis. This suggested that the FITC-LA leakage might have been a result of angiogenesis. To assess the possible role of angiogenesis in DA neuron loss, we treated mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on the following day treated with cyRGDfV, a cyclic peptide that binds to integrin αvβ3 and prevents angiogenesis. Post-treatment for 3 days (b.i.d.) with cyRGDfV blocked the MPTP-induced upregulation of integrin β3 immunoreactivity (a marker for angiogenesis), leakage of FITC-LA into brain parenchyma (a marker for BBB disruption) as well as the down regulation of Zona Occludin-1 (ZO-1; a marker for tight junction integrity). In addition, cyRGDfV also completely prevented tyrosine hydroxylase immunoreactive cell loss (a marker for DA neurons) and markedly attenuated the up-regulation of activated microglia (Iba1 cell counts and morphology). These data suggest that cyRGDfV, and perhaps other anti-angiogenic drugs, are neuroprotective following acute MPTP treatment and may suggest that compensatory angiogenesis and BBB dysfunction may contribute to inflammation and DA neuron loss.
authors.affiliation: Department of Pharmacology, Rush University, Chicago, IL 60612, USA.
authors.forename: Aditiben
authors.initials: A
authors.lastname: Patel
authors.forename: Giuseppe V
authors.initials: GV
authors.lastname: Toia
authors.forename: Kalea
authors.initials: K
authors.lastname: Colletta
authors.forename: Brinda Desai
authors.initials: BD
authors.lastname: Bradaric
authors.forename: Paul M
authors.initials: PM
authors.lastname: Carvey
authors.forename: Bill
authors.initials: B
authors.lastname: Hendey
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D018696:Neuroprotective Agents; D010456:Peptides, Cyclic; C092113:cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl); D004298:Dopamine