Affiliations: [a] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [b] Department of Chemistry, University of Kentucky, Lexington, KY, USA | [c] Department of Pathology and Neurology, University of Kentucky, Lexington, KY, USA
Correspondence:
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Corresponding author: Mark A. Lovell, 135 Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY 40536-0230. Tel.: +1 859 257 1412 x 251; Fax: +1 859 323 2866; E-mail: malove2@pop.uky.edu.
Abstract: Current evidence supports the role of oxidative stress in the pathogenesis of neuron degeneration in Alzheimer's disease (AD). α-Lipoic acid (LA), an essential cofactor in mitochondrial dehydrogenase reactions, functions as an antioxidant and reduces oxidative stress in aged animals. Here, we describe the effects of LA and its reduced form, dihydrolipoic acid (DHLA), in neuron cultures treated with amyloid β-peptide (Aβ 25-35) and iron/hydrogen peroxide (Fe/H2O2). Pretreatment of dissociated primary hippocampal cultures with LA significantly protected against Aβ and Fe/H2O2toxicity. In contrast, concomitant treatment of cultures with LA and Fe/H2O2 significantly potentiated the toxicity. Decreased cell survival in cultures treated concomitantly with LA and Fe/H2O2correlated with increased free radical production measured by dichlorofluorescein fluorescence. Treatment of cortical neurons with DHLA significantly protected glucose-transport against Fe/H2O2 or β-mediated decreases although treatment with LA did not provide protection. These data suggest that DHLA, the reduced form of LA, significantly protects against both Aβ and Fe/H2O2 mediated toxicity. The data also suggest that concomitant exposure to LA and Fe/H2O2significantly potentiates the oxidative stress. Overall, these data suggest that the oxidation state of LA is critical to its function and that in the absence of studies of LA/DHLA equilibria in human brain the use of LA as an antioxidant in disorders where there is increased Fe such as AD is of questionable efficacy.
