| First Author | Omouendze PL | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 8 | Pages | e71263 |
| PubMed ID | 23940734 | Mgi Jnum | J:205906 |
| Mgi Id | MGI:5546591 | Doi | 10.1371/journal.pone.0071263 |
| Citation | Omouendze PL, et al. (2013) Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels. PLoS One 8(8):e71263 |
| abstractText | Hypoxia-ischemia (HI) and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA) participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9) activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1) genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O(2)). Excitotoxic lesions were produced by intra parenchymal cortical (i.c.) injections of 10 microg ibotenate (Ibo). Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA(-)/(-) and enhanced in PAI-1(-)/(-) mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA(-)/(-) mice. In PAI-1(-)/(-) mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1(-)/(-) and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 microM) induced DQ-gelatin activation in vessels. The effect was not detected in t-PA(-)/(-) mice, but was restored by concomitant exposure to recombinant t-PA (20 microg/mL). In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have neuroprotection potential against neonatal brain injuries. |
