Effects of Alcohol on Histone Deacetylase 2 (HDAC2) and the Neuroprotective Role of Trichostatin A (TSA)

Department of Immunology, Florida International University, Miami, FL 33199, USA.
Alcoholism Clinical and Experimental Research (Impact Factor: 3.21). 03/2011; 35(8):1550-6. DOI: 10.1111/j.1530-0277.2011.01492.x
Source: PubMed


Previous studies have implicated histone deacetylases (HDACs) and HDAC inhibitors (HDIs) such as trichostatin A (TSA) in the regulation of gene expression during drug addiction. Furthermore, an increase in HDAC activity has been linked to neurodegeneration. Alcohol has also been shown to promote abundant generation of reactive oxygen species (ROS) resulting in oxidative stress. TSA inhibits HDACs and has been shown to be neuroprotective in other neurodegenerative disease models. Although HDACs and HDIs have been associated with drug addiction, there is no evidence of the neurodegenerative role of HDAC2 and neuroprotective role of TSA in alcohol addiction. Therefore, we hypothesize that alcohol modulates HDAC2 through mechanisms involving oxidative stress.
To test our hypothesis, the human neuronal cell line, SK-N-MC, was treated with different concentrations of ethanol (EtOH); HDAC2 gene and protein expression were assessed at different time points. Pharmacological inhibition of HDAC2 with TSA was evaluated at the gene level using qRT-PCR and at the protein level using Western blot and flow cytometry. ROS production was measured with a fluorescence microplate reader and fluorescence microscopy.
Our results showed a dose-dependent increase in HDAC2 expression with EtOH treatment. Additionally, alcohol significantly induced ROS, and pharmacological inhibition of HDAC2 with TSA was shown to be neuroprotective by significantly inhibiting HDAC2 and ROS.
These results suggest that EtOH can upregulate HDAC2 through mechanisms involving oxidative stress and HDACs may play an important role in alcohol use disorders (AUDs). Moreover, the use of HDIs may be of therapeutic significance for the treatment of neurodegenerative disorders including AUDs.

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Available from: Marisela Agudelo
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    • "It is also important to note that HDACs may have roles beyond just the behaviors observed after injections of amphetamine-like drugs which are known neurotoxic agents that induced oxidative stress (Cadet et al. 2007). For example, inhibition of Class I and II HDACs by Trichostatin A (TSA) has neuroprotective effects against EtOHinduced overproduction of reactive oxygen species in human neuronal cells (Agudelo et al. 2011). METH-induced deacetylation of a-tubulin, an indicator of cellular structural loss, in endothelial cells was also shown to be preventable by treatment with the HDAC inhibitor, TSA (Fernandes et al. 2015). "
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    • "ved as a positive control and Catalase as an antioxidant . Data are expressed as mean ± SE of relative fluorescence units ( RFU ) values of four independent experiments . The statistical significance were expressed as p values ( * * p < 0 . 0001 ) . end of the incubation , cells were used to perform ROS assay as per previously published protocol ( Agudelo et al . , 2011 ) . In this study , we have observed an increase in the ROS productions after treatment with HIV - 1 and / or cocaine , which indicates that there is a certain amount of ROS imbalance in SK - N - MC cells after cocaine treatment and HIV - 1 exposure . Fluorescence images were captured with an Olympus IX51 microscope indicating the reten"
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    • "We recently demonstrated alteration of histone H3 acetylation levels in several brain regions from the reward circuit of rats made dependent to alcohol after chronic and intermittent exposure to ethanol vapor (Simon-O'Brien et al., 2014). In neuronal cell line culture, ethanol was shown to induce HDAC expression (Agudelo et al., 2011, 2012). In mouse and rat brain, numerous studies reported epigenetic alterations following ethanol exposure (Pandey et al., 2008; Pascual et al., 2012; Starkman et al., 2012; Warnault et al., 2013). "
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