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

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Free Radical Biology and Medicine (Impact Factor: 5.71). 11/2010; 49(10):1494-504. DOI: 10.1016/j.freeradbiomed.2010.08.011
Source: PubMed

ABSTRACT The studies presented here demonstrate the protective effect of acetyl-L-carnitine (ALC) against alcohol-induced 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 NOX-expressing 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.

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    • "These results were similar to the report by Dong et al. (2009) who found that PCP could induce apoptosis in primary hepatocytes of goldfish (Carassius carassius), which might be because these chlorophenols have same target points. ALC, an acetylated derivative of l-carnitine, has been shown to protect cells from oxidative injury (Rump et al., 2010), suppress the oxidative stress in and around mitochondria, and finally prevent the mitochondrial signaling pathway which leads to apoptosis (Zhu et al., 2008). "
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    • "Deposition of these immune cells at the site of BBB oxidative injury in the microvessel walls is expected to exacerbate the brain vascular inflammation and neuroinflammatory complication in alcohol abuse. Thus, neuroinflammation is a complex integration of inflammatory process involving ingression of immune cells into the brain via endothelium and a subsequent activation of astroglial cells at the expense of neuronal loss that we demonstrated recently in mouse model chronic alcohol intake (Floreani et al., 2010; Haorah et al., 2007a; Haorah et al., 2008a; Rump et al., 2010). Chronic neuroinflammation is a pathologic index of neurological diseases such as multiple sclerosis and stroke. "
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    • "The stabilization of glucose uptake, GLUT1 protein levels, and BBB integrity by ALC demonstrates the beneficial effect for improving the deleterious health condition of alcohol abusers. The complete penetration of ALC across the BBB (Kido et al. 2001) and our recent findings on neuroprotective mechanisms of ALC from alcohol-induced oxidative damage in the brain (Rump et al. 2010) strongly advocate the attractive therapeutic application for chronic alcohol abusers. ALC would stabilize glycosylation of GLUT1 protein by donating acetyl group to glucosamine so as to enhance the activity of acetylglucosamine, which glycosylates GLUT1 protein. "
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