Hypoxanthine Induces Neuroenergetic Impairment and Cell Death in Striatum of Young Adult Wistar Rats
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Hypoxanthine is the major purine involved in the salvage pathway of purines in the brain. High levels of hypoxanthine are characteristic of Lesch–Nyhan Disease. Since hypoxanthine is a purine closely related to ATP formation, the aim of this study was to investigate the effect of intrastriatal hypoxanthine administration on neuroenergetic parameters (pyruvate kinase, succinate dehydrogenase, complex II, cytochrome c oxidase, and ATP levels) and mitochondrial function (mitochondrial mass and membrane potential) in striatum of rats. We also evaluated the effect of cell death parameters (necrosis and apoptosis). Wistar rats of 60 days of life underwent stereotactic surgery and were divided into two groups: control (infusion of saline 0.9%) and hypoxanthine (10 μM). Intrastriatal hypoxanthine administration did not alter pyruvate kinase activity, but increased succinate dehydrogenase and complex II activities and diminished cytochrome c oxidase activity and immunocontent. Hypoxanthine injection decreased the percentage of cells with mitochondrial membrane label and increased mitochondrial membrane potential labeling. There was a decrease in the number of live cells and an increase in the number of apoptotic cells by caused hypoxanthine. Our findings show that intrastriatal hypoxanthine administration altered neuroenergetic parameters, and caused mitochondrial dysfunction and cell death by apoptosis, suggesting that these processes may be associated, at least in part, with neurological symptoms found in patients with Lesch–Nyhan Disease.
KeywordsHypoxanthine Neuroenergetic ATP Apoptosis
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil).
Compliance with Ethical Standards
Animal care followed the Guide for Care and Use of Laboratory Animals (NIH publication number 80-23 revised 1996) and the recommendations for animal care of the Brazilian Society for Neuroscience and Behavior. The project was approved by the local ethics committee (no. 25717).
Conflict of Interest
The authors declare that there are no conflicts of interest.
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