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Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro.
Brain Res Bull. 2012 Mar 10; 87(4-5):397-405.BR

Abstract

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD seem to be related to oxidative stress, excitotoxicity and misbalance in energetic metabolism. In this study we evaluated the potential relationship between energetic impairment, excitotoxicity and oxidative stress in rat striatal slices exposed to quinolinic acid (QA; as an excitotoxic model), 3-nitropropionic acid (3-NP; as an inhibitor of mitochondrial succinate dehydrogenase), as well as a combined model produced by the co-administration of these two toxins at subtoxic concentrations. We took advantage of the direct antioxidant/scavenger properties of Probucol in order to investigate the role of reactive oxygen species (ROS) in mediating the toxicity of both compounds alone or in association. Experiments with MK-801 (a NMDA type glutamate receptor antagonist) and succinate (an energy precursor agent) were also performed in an attempt to better comprehend the mechanisms of damage and neuroprotection. QA (1 mM), 3-NP (1 mM) and QA plus 3-NP (0.1 mM of both) significantly induced mitochondrial dysfunction and produced an increase in ROS generation, as well as a significant increase in lipid peroxidation in striatal slices. Probucol (10 and 30 μM) prevented ROS formation and lipid peroxidation in all used models, but did not protect against the mitochondrial dysfunction induced by 3-NP (only by QA or QA plus 3-NP). Sodium succinate (1 mM) protected the striatal slices only against 3-NP-induced mitochondrial dysfunction. On the other hand, MK-801 protected against mitochondrial dysfunction in all used models. Our data suggest that the two studied toxic models (QA and 3-NP) or the combined model (QA plus 3-NP) can generate complex patterns of damage, which involve metabolic compromise, ROS formation, and oxidative stress. Moreover, a partial inhibition of SDH by subtoxic 3-NP and moderate excitotoxicty by subtoxic QA are potentiated when both agents are associated. The toxic action of QA plus 3-NP seems to be involved with Ca2+ metabolism and ROS formation, and can be prevented or attenuated by antioxidant/scavenger compounds and NMDAr antagonists.

Authors+Show Affiliations

Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil. dirleise@yahoo.com.brNo 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

22245028

Citation

Colle, Dirleise, et al. "Probucol Modulates Oxidative Stress and Excitotoxicity in Huntington's Disease Models in Vitro." Brain Research Bulletin, vol. 87, no. 4-5, 2012, pp. 397-405.
Colle D, Hartwig JM, Soares FA, et al. Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro. Brain Res Bull. 2012;87(4-5):397-405.
Colle, D., Hartwig, J. M., Soares, F. A., & Farina, M. (2012). Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro. Brain Research Bulletin, 87(4-5), 397-405. https://doi.org/10.1016/j.brainresbull.2012.01.003
Colle D, et al. Probucol Modulates Oxidative Stress and Excitotoxicity in Huntington's Disease Models in Vitro. Brain Res Bull. 2012 Mar 10;87(4-5):397-405. PubMed PMID: 22245028.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro. AU - Colle,Dirleise, AU - Hartwig,Juliana M, AU - Soares,Félix A Antunes, AU - Farina,Marcelo, Y1 - 2012/01/11/ PY - 2011/10/21/received PY - 2011/12/27/revised PY - 2012/01/01/accepted PY - 2012/1/17/entrez PY - 2012/1/17/pubmed PY - 2012/6/23/medline SP - 397 EP - 405 JF - Brain research bulletin JO - Brain Res Bull VL - 87 IS - 4-5 N2 - Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD seem to be related to oxidative stress, excitotoxicity and misbalance in energetic metabolism. In this study we evaluated the potential relationship between energetic impairment, excitotoxicity and oxidative stress in rat striatal slices exposed to quinolinic acid (QA; as an excitotoxic model), 3-nitropropionic acid (3-NP; as an inhibitor of mitochondrial succinate dehydrogenase), as well as a combined model produced by the co-administration of these two toxins at subtoxic concentrations. We took advantage of the direct antioxidant/scavenger properties of Probucol in order to investigate the role of reactive oxygen species (ROS) in mediating the toxicity of both compounds alone or in association. Experiments with MK-801 (a NMDA type glutamate receptor antagonist) and succinate (an energy precursor agent) were also performed in an attempt to better comprehend the mechanisms of damage and neuroprotection. QA (1 mM), 3-NP (1 mM) and QA plus 3-NP (0.1 mM of both) significantly induced mitochondrial dysfunction and produced an increase in ROS generation, as well as a significant increase in lipid peroxidation in striatal slices. Probucol (10 and 30 μM) prevented ROS formation and lipid peroxidation in all used models, but did not protect against the mitochondrial dysfunction induced by 3-NP (only by QA or QA plus 3-NP). Sodium succinate (1 mM) protected the striatal slices only against 3-NP-induced mitochondrial dysfunction. On the other hand, MK-801 protected against mitochondrial dysfunction in all used models. Our data suggest that the two studied toxic models (QA and 3-NP) or the combined model (QA plus 3-NP) can generate complex patterns of damage, which involve metabolic compromise, ROS formation, and oxidative stress. Moreover, a partial inhibition of SDH by subtoxic 3-NP and moderate excitotoxicty by subtoxic QA are potentiated when both agents are associated. The toxic action of QA plus 3-NP seems to be involved with Ca2+ metabolism and ROS formation, and can be prevented or attenuated by antioxidant/scavenger compounds and NMDAr antagonists. SN - 1873-2747 UR - https://www.unboundmedicine.com/medline/citation/22245028/Probucol_modulates_oxidative_stress_and_excitotoxicity_in_Huntington's_disease_models_in_vitro_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0361-9230(12)00004-4 DB - PRIME DP - Unbound Medicine ER -