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The Journal of Neuroscience, February 25, 2009, 29(8):2588-2596; doi:10.1523/JNEUROSCI.5832-08.2009

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Neurobiology of Disease
Developmental Shift of Cyclophilin D Contribution to Hypoxic-Ischemic Brain Injury

Xiaoyang Wang,^1,4 Ylva Carlsson,^1,7 * Emy Basso,^5 * Changlian Zhu,^2,4 Catherine I. Rousset,^1,8 Andrea Rasola,⁵ Bengt R. Johansson,³ Klas Blomgren,² Carina Mallard,¹ Paolo Bernardi,⁵ Michael A. Forte,⁶ and Henrik Hagberg^1,7,8

¹Perinatal Center and ²Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, and ³The Electron Microscopy Unit, Institute for Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden, ⁴Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, 450052 Zhengzhou, China, ⁵Consiglio Nazionale delle Ricerche, Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy, ⁶Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, ⁷Perinatal Center, Department of Obstetrics and Gynecology, Sahlgrenska Academy, SE-416 84 Gothenburg, Sweden, and ⁸Institute of Reproductive and Developmental Biology, Imperial College, London W12 0NN, United Kingdom

Correspondence should be addressed to Dr. Xiaoyang Wang, Perinatal Center, Department of Physiology, University of Gothenburg, Box 432, SE-405 30 Gothenburg, Sweden. Email: xiaoyang.wang{at}fysiologi.gu.se

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.

Key words: brain injury; hypoxia-ischemia; mitochondria; development; cyclophilin D; cell death

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Received Dec. 8, 2008; accepted Dec. 23, 2008.

Correspondence should be addressed to Dr. Xiaoyang Wang, Perinatal Center, Department of Physiology, University of Gothenburg, Box 432, SE-405 30 Gothenburg, Sweden. Email: xiaoyang.wang{at}fysiologi.gu.se

This article has been cited by other articles:

				H. Hagberg, C. Mallard, C. I. Rousset, and Xiaoyang Wang Apoptotic Mechanisms in the Immature Brain: Involvement of Mitochondria J Child Neurol, September 1, 2009; 24(9): 1141 - 1146. [Abstract] [PDF]

				K. Devalaraja-Narashimha, A. M. Diener, and B. J. Padanilam Cyclophilin D gene ablation protects mice from ischemic renal injury Am J Physiol Renal Physiol, September 1, 2009; 297(3): F749 - F759. [Abstract] [Full Text] [PDF]

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