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Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain alpha-keto acids accumulating in maple syrup urine disease.
Cell Mol Neurobiol. 2006 Feb; 26(1):67-79.CM

Abstract

Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV), and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) in tissues and biological fluids is the biochemical hallmark of patients affected by the neurometabolic disorder known as maple syrup urine disease (MSUD). Considering that brain energy metabolism is possibly altered in MSUD, the objective of this study was to determine creatine kinase (CK) activity, a key enzyme of energy homeostasis, in C6 glioma cells exposed to BCKA. The cells were incubated with 1, 5, or 10 mM BCKA for 3 h and the CK activity measured afterwards. The results indicated that the BCKA significantly inhibited CK activity at all tested concentrations. Furthermore, the inhibition caused by the BCKA on CK activity was totally prevented by preincubation with the energetic substrate creatine and by coincubation with the N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, indicating that deficit of energy and nitric oxide (NO) are involved in these effects. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble Vitamin E) were not able to prevent CK inhibition. In addition, we observed that the C6 cells changed their usual rounded morphology when exposed for 3 h to 10 mM BCKA and that creatine and L-NAME prevented these morphological alterations. Considering the importance of CK for brain metabolism homeostasis, it is conceivable that inhibition of this enzyme by increased levels of BCKA may contribute to the neurodegeneration of MSUD patients.

Authors+Show Affiliations

Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 anexo, 90035-003, Porto Alegre, RS, Brazil. csfunchal@yahoo.com.brNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16633902

Citation

Funchal, Cláudia, et al. "Creatine and Antioxidant Treatment Prevent the Inhibition of Creatine Kinase Activity and the Morphological Alterations of C6 Glioma Cells Induced By the Branched-chain Alpha-keto Acids Accumulating in Maple Syrup Urine Disease." Cellular and Molecular Neurobiology, vol. 26, no. 1, 2006, pp. 67-79.
Funchal C, Schuck PF, Santos AQ, et al. Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Cell Mol Neurobiol. 2006;26(1):67-79.
Funchal, C., Schuck, P. F., Santos, A. Q., Jacques-Silva, M. C., Gottfried, C., Pessoa-Pureur, R., & Wajner, M. (2006). Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Cellular and Molecular Neurobiology, 26(1), 67-79.
Funchal C, et al. Creatine and Antioxidant Treatment Prevent the Inhibition of Creatine Kinase Activity and the Morphological Alterations of C6 Glioma Cells Induced By the Branched-chain Alpha-keto Acids Accumulating in Maple Syrup Urine Disease. Cell Mol Neurobiol. 2006;26(1):67-79. PubMed PMID: 16633902.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. AU - Funchal,Cláudia, AU - Schuck,Patrícia Fernanda, AU - Santos,André Quincozes Dos, AU - Jacques-Silva,Maria Caroline, AU - Gottfried,Carmem, AU - Pessoa-Pureur,Regina, AU - Wajner,Moacir, PY - 2005/05/31/received PY - 2005/10/14/accepted PY - 2006/4/25/pubmed PY - 2006/7/18/medline PY - 2006/4/25/entrez SP - 67 EP - 79 JF - Cellular and molecular neurobiology JO - Cell Mol Neurobiol VL - 26 IS - 1 N2 - Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV), and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) in tissues and biological fluids is the biochemical hallmark of patients affected by the neurometabolic disorder known as maple syrup urine disease (MSUD). Considering that brain energy metabolism is possibly altered in MSUD, the objective of this study was to determine creatine kinase (CK) activity, a key enzyme of energy homeostasis, in C6 glioma cells exposed to BCKA. The cells were incubated with 1, 5, or 10 mM BCKA for 3 h and the CK activity measured afterwards. The results indicated that the BCKA significantly inhibited CK activity at all tested concentrations. Furthermore, the inhibition caused by the BCKA on CK activity was totally prevented by preincubation with the energetic substrate creatine and by coincubation with the N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, indicating that deficit of energy and nitric oxide (NO) are involved in these effects. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble Vitamin E) were not able to prevent CK inhibition. In addition, we observed that the C6 cells changed their usual rounded morphology when exposed for 3 h to 10 mM BCKA and that creatine and L-NAME prevented these morphological alterations. Considering the importance of CK for brain metabolism homeostasis, it is conceivable that inhibition of this enzyme by increased levels of BCKA may contribute to the neurodegeneration of MSUD patients. SN - 0272-4340 UR - https://www.unboundmedicine.com/medline/citation/16633902/Creatine_and_antioxidant_treatment_prevent_the_inhibition_of_creatine_kinase_activity_and_the_morphological_alterations_of_C6_glioma_cells_induced_by_the_branched_chain_alpha_keto_acids_accumulating_in_maple_syrup_urine_disease_ L2 - https://doi.org/10.1007/s10571-006-9098-9 DB - PRIME DP - Unbound Medicine ER -