%0 Journal Article
%T Xanthine Oxidase Does Not Contribute to Apoptosis after Brain Hypoxia-Ischemia in Immature Rabbits
%A Anthony Moretti
%A Alma Ramirez
%A Richard Mink
%J ISRN Neuroscience
%D 2013
%R 10.1155/2013/253093
%X Background. The mechanisms involving the initiation of apoptosis after brain hypoxia-ischemia through caspase activation are not fully defined. Oxygen free radicals may be an important mediator of caspase initiation with reactive oxygen species generated by xanthine oxidase (XO) being one potential source. The purpose of this study was to examine the role of XO in apoptosis after global cerebral injury. Methods. Immature rabbits were subjected to 8 minutes hypoxia and 8 minutes ischemia and then 4 hours of reperfusion. In one group ( ), the XO substrate xanthine was infused to generate more oxygen free radicals to promote apoptosis while in another ( ), the XO inhibitor allopurinol was given to reduce apoptosis by preventing free radical production ( ). Control animals ( ) received the vehicles. Caspase 3, 8, and 9 enzyme activities were measured in the cerebral cortex, hippocampus, cerebellum, thalamus, and caudate. Results. Administration of xanthine increased ( ) caspase 3 activity but only in the hippocampus, and pretreatment with allopurinol did not reduce it. No differences ( ) were found in any other region nor were there any changes in caspases 8 or 9 activities. Conclusion. We conclude that XO is not a major factor in inducing apoptosis after hypoxic-ischemic brain injury. 1. Introduction The reperfusion of previously ischemic tissue is believed to contribute to injury through the generation of free radical species [1, 2]. During hypoxia, ATP is depleted and metabolized through various intermediates to hypoxanthine. When perfusion is reestablished, newly provided oxygen allows for the conversion of hypoxanthine to xanthine, and ultimately to uric acid, by the enzyme xanthine oxidase (XO) [1]. This metabolism of hypoxanthine and xanthine to uric acid by XO has been argued to be a source of oxygen free radicals causing cerebral injury [2¨C5]. However, in various animal models, inhibition of XO with allopurinol before ischemia has yielded inconclusive results [6¨C11]. Hypoxia-ischemia leads to not only necrosis but also apoptosis. Apoptosis is a highly ordered process of programmed cell death that can occur in both normal physiologic remodeling and pathologic processes [12]. This type of cell death can be recognized by several biochemical and morphological markers, such as chromatin condensation, DNA fragmentation, caspase activation, and mitochondrial alterations. Apoptosis may be the primary factor in the prolonged progression of neurodegeneration and cerebral dysfunction hours to days after injury [12, 13]. Evidence suggests that apoptosis after
%U http://www.hindawi.com/journals/isrn.neuroscience/2013/253093/