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Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease.
Neurochem Int. 2006 Dec; 49(7):640-50.NI

Abstract

Maple syrup urine disease (MSUD) is an inherited neurometabolic disorder biochemically characterized by the accumulation of the branched-chain alpha-keto acids (BCKA) alpha-ketoisocaproic (KIC), alpha-keto-beta-methylvaleric (KMV) and alpha-ketoisovaleric (KIV) and their respective branched-chain alpha-amino acids in body fluids and tissues. Affected MSUD patients have predominantly neurological features, including cerebral edema and atrophy whose pathophysiology is not well established. In the present study we investigated the effects of KIC, KMV and KIV on cell morphology, cytoskeleton reorganization, actin immunocontent and on various parameters of oxidative stress, namely total antioxidant reactivity (TAR), glutathione (GSH) and nitric oxide concentrations, and on the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in C6 glioma cells. We initially observed that C6 cultivated cells exposed for 3 h to the BCKA (1 and 10 mM) changed their usual rounded morphology to a fusiform or process-bearing cell appearance, while 24 h exposure to these organic acids elicited massive cell death. Rhodamine-labelled phalloidin analysis revealed that these organic acids induced reorganization of the actin cytoskeleton with no modifications on total actin content. It was also observed that 3h cell exposure to low doses of all BCKA (1 mM) resulted in a marked reduction of the non-enzymatic antioxidant defenses, as determined by TAR and GSH measurements. In addition, KIC provoked a reduced activity of SOD and GPx, whereas KMV caused a diminution of SOD activity. In contrast, CAT activity was not modified by the metabolites. Furthermore, nitric oxide production was significantly increased by all BCKA. Finally, we observed that the morphological features caused by BCKA on C6 cells were prevented by the use of the antioxidants GSH (1.0 mM), alpha-tocopherol (trolox; 10 microM) and Nomega-nitro-L-arginine methyl ester (L-NAME; 500 microM). These results strongly indicate that oxidative stress might be involved in the cell morphological alterations and death, as well as in the cytoskeletal reorganization elicited by the BCKA. It is presumed that these findings are possibly implicated in the neuropathological features observed in patients affected by MSUD.

Authors+Show Affiliations

Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 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 availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16822590

Citation

Funchal, Cláudia, et al. "Morphological Alterations and Induction of Oxidative Stress in Glial Cells Caused By the Branched-chain Alpha-keto Acids Accumulating in Maple Syrup Urine Disease." Neurochemistry International, vol. 49, no. 7, 2006, pp. 640-50.
Funchal C, Latini A, Jacques-Silva MC, et al. Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int. 2006;49(7):640-50.
Funchal, C., Latini, A., Jacques-Silva, M. C., Dos Santos, A. Q., Buzin, L., Gottfried, C., Wajner, M., & Pessoa-Pureur, R. (2006). Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochemistry International, 49(7), 640-50.
Funchal C, et al. Morphological Alterations and Induction of Oxidative Stress in Glial Cells Caused By the Branched-chain Alpha-keto Acids Accumulating in Maple Syrup Urine Disease. Neurochem Int. 2006;49(7):640-50. PubMed PMID: 16822590.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. AU - Funchal,Cláudia, AU - Latini,Alexandra, AU - Jacques-Silva,Maria Caroline, AU - Dos Santos,André Quincozes, AU - Buzin,Luciane, AU - Gottfried,Carmem, AU - Wajner,Moacir, AU - Pessoa-Pureur,Regina, Y1 - 2006/07/05/ PY - 2006/02/08/received PY - 2006/04/17/revised PY - 2006/05/23/accepted PY - 2006/7/11/pubmed PY - 2007/1/6/medline PY - 2006/7/11/entrez SP - 640 EP - 50 JF - Neurochemistry international JO - Neurochem Int VL - 49 IS - 7 N2 - Maple syrup urine disease (MSUD) is an inherited neurometabolic disorder biochemically characterized by the accumulation of the branched-chain alpha-keto acids (BCKA) alpha-ketoisocaproic (KIC), alpha-keto-beta-methylvaleric (KMV) and alpha-ketoisovaleric (KIV) and their respective branched-chain alpha-amino acids in body fluids and tissues. Affected MSUD patients have predominantly neurological features, including cerebral edema and atrophy whose pathophysiology is not well established. In the present study we investigated the effects of KIC, KMV and KIV on cell morphology, cytoskeleton reorganization, actin immunocontent and on various parameters of oxidative stress, namely total antioxidant reactivity (TAR), glutathione (GSH) and nitric oxide concentrations, and on the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in C6 glioma cells. We initially observed that C6 cultivated cells exposed for 3 h to the BCKA (1 and 10 mM) changed their usual rounded morphology to a fusiform or process-bearing cell appearance, while 24 h exposure to these organic acids elicited massive cell death. Rhodamine-labelled phalloidin analysis revealed that these organic acids induced reorganization of the actin cytoskeleton with no modifications on total actin content. It was also observed that 3h cell exposure to low doses of all BCKA (1 mM) resulted in a marked reduction of the non-enzymatic antioxidant defenses, as determined by TAR and GSH measurements. In addition, KIC provoked a reduced activity of SOD and GPx, whereas KMV caused a diminution of SOD activity. In contrast, CAT activity was not modified by the metabolites. Furthermore, nitric oxide production was significantly increased by all BCKA. Finally, we observed that the morphological features caused by BCKA on C6 cells were prevented by the use of the antioxidants GSH (1.0 mM), alpha-tocopherol (trolox; 10 microM) and Nomega-nitro-L-arginine methyl ester (L-NAME; 500 microM). These results strongly indicate that oxidative stress might be involved in the cell morphological alterations and death, as well as in the cytoskeletal reorganization elicited by the BCKA. It is presumed that these findings are possibly implicated in the neuropathological features observed in patients affected by MSUD. SN - 0197-0186 UR - https://www.unboundmedicine.com/medline/citation/16822590/Morphological_alterations_and_induction_of_oxidative_stress_in_glial_cells_caused_by_the_branched_chain_alpha_keto_acids_accumulating_in_maple_syrup_urine_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(06)00193-8 DB - PRIME DP - Unbound Medicine ER -