JOURNAL ARTICLE

Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro

Dirleise Colle, Juliana M Hartwig, Félix A Antunes Soares, Marcelo Farina
Brain Research Bulletin 2012 March 10, 87 (4-5): 397-405
22245028
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
22245028
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"