Role of tissue-plasminogen activator (t-PA) in a mouse model of neonatal white matter lesions: interaction with plasmin inhibitors and anti-inflammatory drugs.
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.
Leroux
P
P
INSERM Avenir Dr. V. Laudenbach, Mécanismes et Traitement des Troubles du Développement Cérébral, School of Medicine and Pharmacy, Rouen University, 22 Boulevard Gambetta, 76183 Rouen, France. philippe.leroux@univ-rouen.fr
Hennebert
O
O
Legros
H
H
Laudenbach
V
V
Carmeliet
P
P
Marret
S
S
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D003560:Cysts / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007051:Ibotenic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use
D018696:Neuroprotective Agents; D007051:Ibotenic Acid; D010959:Tissue Plasminogen Activator