Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain.
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.
Rump
Travis J
TJ
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Muneer
P M Abdul
PMA
Szlachetka
Adam M
AM
Lamb
Allyson
A
Haorei
Catherine
C
Alikunju
Saleena
S
Xiong
Huangui
H
Keblesh
James
J
Liu
Jianuo
J
Zimmerman
Matthew C
MC
Jones
Jocelyn
J
Donohue
Terrence M
TM
Persidsky
Yuri
Y
Haorah
James
J
D000108:Acetylcarnitine / Q000494:pharmacology*; D000447:Aldehydes; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D000431:Ethanol / Q000633:toxicity*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000447:Aldehydes; D018696:Neuroprotective Agents; C002744:3-nitrotyrosine; D000431:Ethanol; D014443:Tyrosine; D000108:Acetylcarnitine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C027576:4-hydroxy-2-nonenal