Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain

Authors

Travis J. Rump, University of Nebraska Medical Center
P. M. Abdul Muneer, University of Nebraska Medical Center
Adam M. Szlachetka, University of Nebraska Medical Center
Allyson Lamb, University of Nebraska Medical Center
Catherine Haorei, University of Nebraska Medical Center
Saleena Alikunju, University of Nebraska Medical Center
Huangui Xiong, University of Nebraska Medical CenterFollow
James Keblesh, University of Nebraska Medical Center
Jianuo Liu, University of Nebraska Medical CenterFollow
Matthew C. Zimmerman, University of Nebraska Medical CenterFollow
Jocelyn Jones, University of Nebraska Medical Center
Terrence M. Donohue Jr., Department of Internal Medicine and Veterans Affairs Medical CenterFollow
Yuri Persidsky, Temple University School of MedicineFollow
James Haorah, University of Nebraska Medical CenterFollow

Date of this Version

2010

Document Type

Article

Citation

Free Radical Biology & Medicine 49 (2010) 1494–1504; doi:10.1016/j.freeradbiomed.2010.08.011

Abstract

The studies presented here demonstrate the protective effect of acetyl-L-carnitine (ALC) against alcoholinduced oxidative neuroinflammation, neuronal degeneration, and impaired neurotransmission. Our findings reveal the cellular and biochemical mechanisms of alcohol-induced oxidative damage in various types of brain cells. Chronic ethanol administration to mice caused an increase in inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine adduct formation in frontal cortical neurons but not in astrocytes from brains of these animals. Interestingly, alcohol administration caused a rather selective activation of NADPH oxidase (NOX), which, in turn, enhanced levels of reactive oxygen species (ROS) and 4-hydroxynonenal, but these were predominantly localized in astrocytes and microglia. Oxidative damage in glial cells was accompanied by their pronounced activation (astrogliosis) and coincident neuronal loss, suggesting that inflammation in glial cells caused neuronal degeneration. Immunohistochemistry studies indicated that alcohol consumption induced different oxidative mediators in different brain cell types. Thus, nitric oxide was mostly detected in iNOS-expressing neurons, whereas ROS were predominantly generated in NOXexpressing glial cells after alcohol ingestion. Assessment of neuronal activity in ex vivo frontal cortical brain tissue slices from ethanol-fed mice showed a reduction in long-term potentiation synaptic transmission compared with slices from controls. Coadministration of ALC with alcohol showed a significant reduction in oxidative damage and neuronal loss and a restoration of synaptic neurotransmission in this brain region, suggesting that ALC protects brain cells from ethanol-induced oxidative injury. These findings suggest the potential clinical utility of ALC as a neuroprotective agent that prevents alcohol-induced brain damage and development of neurological disorders.