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Cysteamine prevents inhibition of thiol-containing enzymes caused by cystine or cystine dimethylester loading in rat brain cortex

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Abstract

Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Considering that thiol-containing enzymes are critical for several metabolic pathways, our main objective was to investigate the effects of cystine or cystine dimethylester load on the thiol-containing enzymes creatine kinase and pyruvate kinase, in the brain cortex of young Wistar rats. The animals were injected twice a day with 1.6 μmol/g body weight of cystine dimethylester or 1μmol/g body weight of cystine and/or 0.46 μmol/g body weight of cysteamine from the 16th to the 20th postpartum day and sacrificed after 12 h. Cystine or cystine dimethylester administration inhibited the two enzyme activities. Co-administration of cysteamine, the drug used to treat cystinotic patients, normalized the two enzyme activities. Lactate dehydrogenase activity, a nonthiol-containing enzyme was not affected by cystine dimethylester administration. Cystine inhibits creatine kinase and pyruvate activities possibly by oxidation of the sulfhydryl groups of the enzymes. Considering that creatine kinase and pyruvate kinase, like other thiol-containing enzymes, are crucial for energy homeostasis and antioxidant defenses, the enzymes inhibition caused by cystine released from lysosomes could be one of the mechanisms of tissue damage in patients with cystinosis.

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Acknowledgements

This work was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e tecnológico (CNPq-Brazil), Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS, RS-Brazil), Programa de Núcleos de Excelência (PRONEX-CNPq /FAPERGS-Brazil) and Rede instituto Brasileiro de Neurociências (FINEP /IBN-Net no. 01.06.0842-00)

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos 2600, CEP 90.035-003, Porto Alegre, Rio Grande do Sul, Brazil

    Virginia Cielo Rech, Luciane Rosa Feksa, Rochele Marisa Müller Fleck, Genaro Azambuja Athaydes, Paula Karina Barcelos Dornelles, Valnes Rodrigues-Junior & Clovis Milton Duval Wannmacher

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  1. Virginia Cielo Rech
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  2. Luciane Rosa Feksa
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Correspondence to Clovis Milton Duval Wannmacher.

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Rech, V.C., Feksa, L.R., Fleck, R.M.M. et al. Cysteamine prevents inhibition of thiol-containing enzymes caused by cystine or cystine dimethylester loading in rat brain cortex. Metab Brain Dis 23, 133–145 (2008). https://doi.org/10.1007/s11011-008-9081-x

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