Postischemic treatment of neonatal cerebral ischemia should target autophagy.

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Version: Author's accepted manuscript
Serval ID
serval:BIB_446DC45428C7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Postischemic treatment of neonatal cerebral ischemia should target autophagy.
Journal
Annals of Neurology
Author(s)
Puyal J., Vaslin A., Mottier V., Clarke P.G.H.
ISSN
1531-8249[electronic]
Publication state
Published
Issued date
2009
Volume
66
Number
3
Pages
378-389
Language
english
Abstract
OBJECTIVE: To evaluate the contributions of autophagic, necrotic, and apoptotic cell death mechanisms after neonatal cerebral ischemia and hence define the most appropriate neuroprotective approach for postischemic therapy. METHODS: Rats were exposed to transient focal cerebral ischemia on postnatal day 12. Some rats were treated by postischemic administration of pan-caspase or autophagy inhibitors. The ischemic brain tissue was studied histologically, biochemically, and ultrastructurally for autophagic, apoptotic, and necrotic markers. RESULTS: Lysosomal and autophagic activities were increased in neurons in the ischemic area from 6 to 24 hours postinjury, as shown by immunohistochemistry against lysosomal-associated membrane protein 1 and cathepsin D, by acid phosphatase histochemistry, by increased expression of autophagosome-specific LC3-II and by punctate LC3 staining. Electron microscopy confirmed the presence of large autolysosomes and putative autophagosomes in neurons. The increases in lysosomal activity and autophagosome formation together demonstrate increased autophagy, which occurred mainly in the border of the lesion, suggesting its involvement in delayed cell death. We also provide evidence for necrosis near the center of the lesion and apoptotic-like cell death in its border, but in nonautophagic cells. Postischemic intracerebroventricular injections of autophagy inhibitor 3-methyladenine strongly reduced the lesion volume (by 46%) even when given >4 hours after the beginning of the ischemia, whereas pan-caspase inhibitors, carbobenzoxy-valyl-alanyl-aspartyl(OMe)-fluoromethylketone and quinoline-val-asp(OMe)-Ch2-O-phenoxy, provided no protection. INTERPRETATION: The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia.
Keywords
Delayed Neuronal Death, Cell-Death, Hypoxia-Ischemia, Focal Ischemia, Rat-Brain, Transient Ischemia, Up-Regulation, Cathepsins B, Kainic Acid, Apoptosis
Pubmed
Web of science
Open Access
Yes
Create date
29/10/2009 10:28
Last modification date
20/08/2019 13:48
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