title: Effects of alcohol on histone deacetylase 2 (HDAC2) and the neuroprotective role of trichostatin A (TSA).
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Immunology, Florida International University, Miami, FL 33199, USA.
authors: Marisela
authors: M
authors: Agudelo
authors: Nimisha
authors: N
authors: Gandhi
authors: Zainulabedin
authors: Z
authors: Saiyed
authors: Vijaya
authors: V
authors: Pichili
authors: Samikkannu
authors: S
authors: Thangavel
authors: Pradnya
authors: P
authors: Khatavkar
authors: Adriana
authors: A
authors: Yndart-Arias
authors: Madhavan
authors: M
authors: Nair
mesh_terms: D002460:Cell Line; D002492:Central Nervous System Depressants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D000431:Ethanol; C012589:trichostatin A; D056464:Histone Deacetylase 2