Stabilization of superoxide dismutase by acetyl-l-carnitine in human brain endothelium during alcohol exposure: Novel protective approach

James Haorah, Nicholas A. Floreani, Bryan Knipe, Yuri Persidsky

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Oxidative damage of the endothelium disrupts the integrity of the blood-brain barrier (BBB). We have shown before that alcohol exposure increases the levels of reactive oxygen species (ROS; superoxide and hydroxyl radical) and nitric oxide (NO) in brain endothelial cells by activating NADPH oxidase and inducible nitric oxide synthase. We hypothesize that impairment of antioxidant systems, such as a reduction in catalase and superoxide dismutase (SOD) activity, by ethanol exposure may elevate the levels of ROS/NO in endothelium, resulting in BBB damage. This study examines whether stabilization of antioxidant enzyme activity results in suppression of ROS levels by anti-inflammatory agents. To address this idea, we determined the effects of ethanol on the kinetic profile of SOD and catalase activity and ROS/NO generation in primary human brain endothelial cells (hBECs). We observed an enhanced production of ROS and NO levels due to the metabolism of ethanol in hBECs. Similar increases were found after exposure of hBECs to acetaldehyde, the major metabolite of ethanol. Ethanol simultaneously augmented ROS generation and the activity of antioxidative enzymes. SOD activity was increased for a much longer period of time than catalase activity. A decline in SOD activity and protein levels preceded elevation of oxidant levels. SOD stabilization by the antioxidant and mitochondria-protecting agent acetyl-L-carnitine (ALC) and the anti-inflammatory agent rosiglitazone suppressed ROS levels, with a marginal increase in NO levels. Mitochondrial membrane protein damage and decreased membrane potential after ethanol exposure indicated mitochondrial injury. These changes were prevented by ALC. Our findings suggest the counteracting mechanisms of oxidants and antioxidants during alcohol-induced oxidative stress at the BBB. The presence of enzymatic stabilizers favors the ROS-neutralizing antioxidant redox of the BBB, suggesting an underlying protective mechanism of NO for brain vascular tone and vasodilation.

Original languageEnglish (US)
Pages (from-to)1601-1609
Number of pages9
JournalFree Radical Biology and Medicine
Volume51
Issue number8
DOIs
StatePublished - Oct 15 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Keywords

  • Antioxidant
  • Brain endothelium
  • Catalase
  • Free radicals
  • Mitochondria
  • Reactive oxygen species
  • Superoxide dismutase

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