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Developmental shift of Cyclophilin D contribution to hypoxic-ischemic brain injury
- Publication Year :
- 2009
-
Abstract
- Cyclophilin D (CypD), a regulator of the mitochondrial membrane permeability transition pore (PTP), enhances Ca2+-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 :
- medicine.medical_specialty
Programmed cell death
Time Factors
Mitochondrion
Article
Cyclophilins
Mice
Bcl-2-associated X protein
Microscopy, Electron, Transmission
Cyclosporin a
Internal medicine
Proto-Oncogene Proteins
medicine
Animals
Caspase
bcl-2-Associated X Protein
Regulation of gene expression
Mice, Knockout
biology
Cell Death
General Neuroscience
Age Factors
Apoptosis Inducing Factor
Brain
Cytochromes c
Gene Expression Regulation, Developmental
Peptide Fragments
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
Endocrinology
Animals, Newborn
Apoptosis
Brain Injuries
Caspases
Hypoxia-Ischemia, Brain
Mitochondrial Membranes
biology.protein
Disease Progression
Apoptosis-inducing factor
Microtubule-Associated Proteins
Cyclophilin D
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....919e0bef6f8650f740c424d8f3c1904e