An angiogenic inhibitor, cyclic RGDfV, attenuates MPTP-induced dopamine neuron toxicity

作者：Patel Aditiben; Toia Giuseppe V; Colletta Kalea; Bradaric Brinda Desai; Carvey Paul M; Hendey Bill^*

来源：Experimental Neurology, 2011, 231(1): 160-170.

DOI：10.1016/j.expneurol.2011.06.004

• Blood brain barrier
• ZO-1
• Neuroinflammation
• Microglia
• Parkinson's disease
• Disease progression
• Angiogenesis

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 alpha v beta 3 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 alpha v beta 3 and prevents angiogenesis. Post-treatment for 3 days (b.i.d.) with cyRGDfV blocked the MPTP-induced upregulation of integrin beta 3 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.

• 出版日期2011-9