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Exp Ther Med. 2014 Feb;7(2):383-388. Epub 2013 Nov 20.

Radiation-induced cytochrome c release and the neuroprotective effects of the pan-caspase inhibitor z-VAD-fmk in the hypoglossal nucleus.

Author information

1
Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Nankai, Tianjin 300192, P.R. China ; Department of Human Anatomy, The Medical School of Inner Mongolia University for the Nationalities, Tongliao, Neimenggu 028041, P.R. China.
2
Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Nankai, Tianjin 300192, P.R. China.

Abstract

Numerous studies have demonstrated that neuronal cell death occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Radiation induces caspase activation fundamentally via the mitochondrial pathway. To investigate the role of caspase, a cell permeable pan-caspase inhibitor, z-VAD-fmk [N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone], was used to investigate the effects of caspase blockade in vivo following irradiation. Adult male Sprague-Dawley rats (weight, 250-300 g) underwent irradiation at room temperature with a 4-Gy dose of radiation. Since z-VAD-fmk does not penetrate the blood-brain barrier, it was applied intracerebroventricularly via a bolus injection (0.2 μg/h for 1 h). Terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) demonstrated that z-VAD-fmk reduced the numbers of TUNEL-positive cells within the hypoglossal nucleus, suggesting that intervention in the caspase cascade following radiation may have therapeutic applications. The caspase inhibitor z-VAD-fmk reduced the expression and activation of caspase-3, caspase-8 and caspase-9 in the irradiated rats, indicating that caspase may be a potential therapeutic target in the treatment of brain radiation injury. Treatment with z-VAD-fmk also reduced the appearance of cytochrome c within the cytosolic fraction following radiation. The hypoglossal nucleus may be used as a model of radiation-induced injury in the central nervous system, providing visual information and displaying apoptotic nuclear morphology.

KEYWORDS:

DIABLO; Smac; X-linked inhibitor of apoptosis protein; cytochrome c; hypoglossal nucleus; radiation; z-VAD-fmk

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