[Prenatal inhibition of intestinal vasoactive peptide and cerebral excitatory lesions in the newborn mouse].
The glutamatergic agent ibotenate induces cortical plate and white matter lesions in the newborn mouse, mimicking brain lesions of the human neonate. In this model, co-treatment with ibotenate and a vasoactive intestinal peptide antagonist (VA) aggravates the excitotoxic lesions, suggesting a protective role of endogenous VIP. On the other hand, prenatal injection of VA is followed by a dramatic depletion of astrocytes in the neocortex. Since astrocytes produce numerous neuronotrophic agents, we studied the consequences of a decreased astrocytic density by prenatal VIP blockade on the excitotoxic brain lesions in newborn mice. Pregnant females were pre-treated with VA during the last 2 days of gestation and ibotenate was intracerebrally injected on postnatal day (P) 2 or P5. When compared to controls, pups pre-treated with VA and injected with ibotenate at P2 displayed a significant reduction of the white matter lesion size while cortical plate lesion was not affected. This protective effect disappeared when ibotenate was injected at P5. White matter protection by VA pre-treatment did not seem to be linked to the decreased astrocytic density since, i) this astrocytic paucity concerns only superficial cortical layers and does not affect white matter, ii) protective effects are only observed at P2 while astrocytic density reduction is observed at P2 and P5. This white matter protection could be secondary to an up-regulation of VIP receptors: an increased density of VIP receptors, which was described in other developmental models following VA treatment, could increase the efficacy of the endogenous VIP after an excitotoxic insult.
Lamboley
G
G
Service de neurologie pédiatrique, hôpital Robert-Debré, Paris, France.
Evrard
P
P
Gressens
P
P
D000818:Animals; D000831:Animals, Newborn; D002547:Cerebral Palsy / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005314:Embryonic and Fetal Development / Q000187:drug effects* / Q000502:physiology*; D018846:Excitatory Amino Acids / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000031:analogs & derivatives; D006801:Humans; D007051:Ibotenic Acid; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011247:Pregnancy; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors* / Q000502:physiology*