Ontogenic study of the influence of tissue plasminogen activator (t-PA) in neonatal excitotoxic brain insult and the subsequent microglia/macrophage activation.
Intracerebral injections of ibotenic acid in neonatal mice produced white and gray matter lesions that mimic some aspects of the acquired cerebral injuries observed in human newborns (i.e. periventricular leukomalacias in preterm newborns and post-ischemic cortical necrosis in at term infants). We have evaluated the effects of tissue plasminogen activator inactivation (t-PA-/-) on the effects of ibotenic acid (0.01-20 microg), and on F4/80 labeling of microglia/macrophages at different stages. Three ontogenic periods have been identified. In mice injected the day of birth, postnatal (P) day 0, ibotenic acid induced neuronal migration disorders together with low local microglial activation in wild-type and t-PA-/- mice. In P2 and P5 mice, ibotenic acid induced diffuse microglial activation in the whole cortex and subcortical areas; e.g. caudate nucleus and septum. In wild-type mice, cystic lesions of the white matter were consistently observed, surrounded by macrophages. In t-PA-/- mice, noncystic lesions filled of macrophages were more frequent than cysts. Macrophages were virtually absent in the gray matter. White and gray matter lesions were reduced in t-PA-/- mice. The plasmin inhibitor aprotinin reduced white and gray matter lesions only in wild-type mice injected with high ibotenic acid doses (2.5-5 microg). During this period, a transient F4/80 immunoreactive cell population was detected in the cingulum. At P10, the salient lesion characteristic was a large gray matter lesion containing macrophage accumulation. Microglial activation was confined to the injection site in the white matter. t-PA-/- mice showed reduced lesion size under high doses (>5 microg) of ibotenic acid. Similarly, aprotinin diminished the lesion in wild-type animals exposed to 10 microg ibotenic acid. These data demonstrate that t-PA and microglia do not actively participate in the migration disorders induced in P0 mice. Conversely, t-PA was implicated in cyst formation in older (P2-P10) mice, and in their subsequent growth. t-PA was also involved in GM lesions, probably through an inflammatory process involving macrophages.
Hennebert
O
O
MERCI, UPRES EA 2122, Faculty of Medicine-Pharmacy, Rouen University, 22 Boulevard Gambetta, 76183 Rouen, France.
Laudenbach
V
V
Laquerriere
A
A
Verney
C
C
Carmeliet
P
P
Marret
S
S
Leroux
P
P
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001921:Brain; D001923:Brain Chemistry; D001927:Brain Diseases / Q000139:chemically induced / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005341:Fibrinolysin / Q000502:physiology; D007051:Ibotenic Acid / Q000633:toxicity*; D007150:Immunohistochemistry; D007267:Injections; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000235:genetics* / Q000502:physiology*
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D007051:Ibotenic Acid; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin