Enhanced autophagy contributes to excitotoxic lesions in a rat model of preterm brain injury.

Détails

Ressource 1Télécharger: s41419-018-0916-z.pdf (2636.28 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_1935027BC6E5
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Enhanced autophagy contributes to excitotoxic lesions in a rat model of preterm brain injury.
Périodique
Cell Death & Disease
Auteur⸱e⸱s
Descloux C., Ginet V., Rummel C., Truttmann A.C., Puyal J.
ISSN
2041-4889 (Electronic)
Statut éditorial
Publié
Date de publication
2018
Peer-reviewed
Oui
Volume
9
Numéro
9
Pages
853
Langue
anglais
Résumé
Cystic periventricular leukomalacia is commonly diagnosed in premature infants, resulting from severe hypoxic-ischemic white matter injury, and also involving some grey matter damage. Very few is known concerning the cell death pathways involved in these types of premature cerebral lesions. Excitotoxicity is a predominant mechanism of hypoxic-ischemic injury in the developing brain. Concomitantly, it has been recently shown that autophagy could be enhanced in excitotoxic conditions switching this physiological intracellular degradation system to a deleterious process. We here investigated the role of autophagy in a validated rodent model of preterm excitotoxic brain damage mimicking in some aspects cystic periventricular leukomalacia. An excitotoxic lesion affecting periventricular white and grey matter was induced by injecting ibotenate, a glutamate analogue, in the subcortical white matter (subcingulum area) of five-day old rat pups. Ibotenate enhanced autophagy in rat brain dying neurons at 24 h as shown by increased presence of autophagosomes (increased LC3-II and LC3-positive dots) and enhanced autophagic degradation (SQSTM1 reduction and increased number and size of lysosomes (LAMP1- and CATHEPSIN B-positive vesicles)). Co-injection of the pharmacological autophagy inhibitor 3-methyladenine prevented not only autophagy induction but also CASPASE-3 activation and calpain-dependent cleavage of SPECTRIN 24 h after the insult, thus providing a strong reduction of the long term brain injury (16 days after ibotenate injection) including lateral ventricle dilatation, decreases in cerebral tissue volume and in subcortical white matter thickness. The autophagy-dependent neuroprotective effect of 3-methyladenine was confirmed in primary cortical neuronal cultures using not only pharmacological but also genetic autophagy inhibition of the ibotenate-induced autophagy. Strategies inhibiting autophagy could then represent a promising neuroprotective approach in the context of severe preterm brain injuries.
Pubmed
Web of science
Open Access
Oui
Création de la notice
04/09/2018 7:49
Dernière modification de la notice
20/08/2019 12:49
Données d'usage