Editors' ChoiceAlcohol Toxicity

Alcohol Takes Its Toll on the Brain

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Science Translational Medicine  07 Jul 2010:
Vol. 2, Issue 39, pp. 39ec108
DOI: 10.1126/scitranslmed.3001431

Ethanol is the most widely used psychotropic substance in the world, and chronic ethanol abuse leads to harmful changes in virtually every organ system in the body. Notably, this includes the brain, where consumption of alcohol can lead to irreversible changes in cognition, mood, and behavior. Although it has been known that this often involves degenerative, inflammatory-mediated processes, their precise nature has not been characterized. In a recent article, Alfonso-Loeches and colleagues report that much of the ethanol-induced inflammation in the brain depends on signaling through Toll-like receptors (TLRs). These receptors participate in innate immunity responses to infection but are also implicated in reactions to injury and degeneration in the brain. Using primary cultures of rodent astrocytes, these investigators found that TLR4-deficient cells failed to exhibit ethanol-induced activation of the nuclear factor NFκB-p65 and microtubule-associated protein kinase pathways, which regulate inflammatory mediators and cytokines. In the cerebral cortex of mice in which TLR4 had been knocked out, there was less ethanol-induced glial fibrillary acid protein, which is an astrocyte-specific intermediate filament that contributes to neurodegeneration. Furthermore, TLR4-deficient mice that were chronically fed ethanol showed no induction of inflammatory mediators COX-2 and inducible nitric oxide synthase in the cerebral cortex, unlike wild-type mice with the same ethanol intake. These changes were confined to glia, including both astrocytes and microglia. Mice in which TLR4 had been knocked out also lacked increased expression of the proteolytic enzyme caspase-3, suggesting that TLR4-mediated glial activation may lead to neuronal cell death via apoptosis. These results suggest that TLRs play a critical role in alcohol-related brain changes, just as they have been previously implicated in Alzheimer’s disease, ischemic brain injury, and HIV infection. This opens up a route for drug development, by targeting these receptors and their downstream pathways, so as to potentially intervene in this costly illness.

S.Alfonso-Loeches et al., Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J. Neurosci. 30, 8285–8295 (2010). [Abstract]

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