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Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2009 Feb 25; Vol. 29 (8), pp. 2588-96. - Publication Year :
- 2009
-
Abstract
- Cyclophilin D (CypD), a regulator of the mitochondrial membrane permeability transition pore (PTP), enhances Ca(2+)-induced mitochondrial permeabilization and cell death in the brain. However, the role of CypD in hypoxic-ischemic (HI) brain injury at different developmental ages is unknown. At postnatal day (P) 9 or P60, littermates of CypD-deficient [knock-out (KO)], wild-type (WT), and heterozygous mice were subjected to HI, and brain injury was evaluated 7 d after HI. CypD deficiency resulted in a significant reduction of HI brain injury at P60 but worsened injury at P9. After HI, caspase-dependent and -independent cell death pathways were more induced in P9 CypD KO mice than in WT controls, and apoptotic activation was minimal at P60. The PTP had a considerably higher induction threshold and lower sensitivity to cyclosporin A in neonatal versus adult mice. On the contrary, Bax inhibition markedly reduced caspase activation and brain injury in immature mice but was ineffective in the adult brain. Our findings suggest that CypD/PTP is critical for the development of brain injury in the adult, whereas Bax-dependent mechanisms prevail in the immature brain. The role of CypD in HI shifts from a predominantly prosurvival protein in the immature to a cell death mediator in the adult brain.
- Subjects :
- Age Factors
Animals
Animals, Newborn
Apoptosis Inducing Factor metabolism
Brain metabolism
Brain pathology
Brain ultrastructure
Brain Injuries genetics
Brain Injuries pathology
Caspases metabolism
Cell Death drug effects
Cell Death physiology
Peptidyl-Prolyl Isomerase F
Cyclophilins deficiency
Cytochromes c metabolism
Disease Models, Animal
Disease Progression
Gene Expression Regulation, Developmental drug effects
Gene Expression Regulation, Developmental genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron, Transmission methods
Microtubule-Associated Proteins metabolism
Mitochondrial Membranes drug effects
Mitochondrial Membranes metabolism
Mitochondrial Membranes physiology
Mitochondrial Membranes ultrastructure
Peptide Fragments pharmacology
Proto-Oncogene Proteins pharmacology
Time Factors
bcl-2-Associated X Protein metabolism
Brain Injuries etiology
Brain Injuries metabolism
Cyclophilins physiology
Hypoxia-Ischemia, Brain complications
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 29
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 19244535
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.5832-08.2009