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Title: Role of tissue-plasminogen activator (t-PA) in a mouse model of neonatal white matter lesions: interaction with plasmin inhibitors and anti-inflammatory drugs
Authors: Leroux, P ×
Hennebert, O
Legros, H
Laudenbach, V
Carmeliet, Peter
Marret, S #
Issue Date: May-2007
Series Title: Neuroscience vol:146 issue:2 pages:670-8
Abstract: Ibotenic acid injected intracerebrally over a broad dose range to 5-day-old mice induces cystic white matter (WM) lesions that mimic periventricular leukomalacia (PVL) of preterm infants. With both low (0.1 mug) and high (5 mug) ibotenic acid doses, tissue-plasminogen activator (t-PA) is involved in cyst formation. Subsequent cyst growth depends on high doses. We evaluated the effects of human recombinant tissue-plasminogen activator (hrt-PA), plasmin inhibitors (tranexamic acid, alpha2-antiplasmin, and aprotinin), and anti-inflammatory drugs (betamethasone, NS-398) in wild-type and t-PA(-/-) mice given high-dose or low-dose ibotenic acid. Intracerebral hrt-PA induced WM cystic lesions in t-PA(-/-) mice and had an additive effect when co-injected with high-dose ibotenic acid. Plasmin inhibitors reduced lesion growth in wild-type mice given high-dose, but not low-dose, ibotenic acid but had no effect in t-PA(-/-) mice. Similarly the anti-inflammatory drugs betamethasone and NS-398 (a cyclooxygenase 2 and NFkappaB inhibitor) were neuroprotective in wild-type animals exposed to high-dose, but not low-dose, ibotenic acid. Thus, the t-PA-dependent effect of low-dose ibotenic acid on cyst formation appeared independent from plasmin activity or inflammation. Conversely, a t-PA-dependent inflammatory process occurred with high-dose ibotenic acid. Potential strategies for PVL in preterm neonates may include fibrinolytic monitoring for prevention and anti-inflammatory agents for treatment.
URI: 
ISSN: 0306-4522
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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