Introduction: Repeated exposure to high doses of alcohol triggers neuroinflammatory processes that contribute to craving and mood dysfunction in alcohol use disorder (AUD). The upregulation of the translocator protein (TSPO) is considered a biomarker of neuroinflammation, and TSPO ligands have been used as neuroimaging biomarkers of neuroinflammation. Epigenetic mechanisms are also implicated in neuroinflammatory responses to alcohol, and elevated expression of HDAC2 and HDAC6 has been reported in the brain of animals exposed to chronic alcohol.
Methods: The present study examined the transcriptional regulation of TSPO, HDAC2, and HDAC6 in human postmortem brain tissue from males previously diagnosed with AUD (n = 11) compared to age-matched nondependent males (n = 13) in four brain regions relevant to AUD: prefrontal cortex (PFC), nucleus accumbens (NAc), hippocampus (HPP), and amygdala (AMY).
Results: Translocator protein mRNA levels in AMY and PFC and HDAC2 and HDAC6 mRNA levels in AMY were upregulated in AUD compared to controls. In AMY, TSPO mRNA levels were positively associated with HDAC2 and HDAC6 mRNA levels, suggesting a possible regulation of TSPO by HDAC2 and HDAC6 in this brain region. In contrast, there were no group differences for TSPO, HDAC2, and HDAC6 in NAc and HPP.
Conclusion: Our study is the first to find upregulated TSPO mRNA levels in AMY and PFC in postmortem brains from AUD consistent with neuroinflammation, and in the amygdala, they implicate epigenetic regulation of TSPO by HDAC2 and HDAC6.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882159 | PMC |
| http://dx.doi.org/10.1002/brb3.1961 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Chemoproteomics Sheds Light on Epigenetic Targets of [C]Martinostat in the Human Brain.
ACS Chem Neurosci
February 2025
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
Initiation of research programs to investigate binding specificity based on in vivo positron emission tomography (PET) imaging results can provide rich opportunities to improve data interpretation, gain biological insight, and inform hypothesis development. Here, we profile the binding specificity of the neuroepigenetic imaging probe, [C]Martinostat. In vivo neuroimaging studies using [C]Martinostat have uncovered differential regional uptake in relation to age and biological sex and in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and low-back pain compared to healthy controls.
View Article and Find Full Text PDFProbing class I histone deacetylases (HDAC) with proteolysis targeting chimera (PROTAC) for the development of highly potent and selective degraders.
Bioorg Chem
December 2024
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany.
Class I HDACs are considered promising targets for cancer due to their role in epigenetic modifications. The main challenges in developing a new, potent and non-toxic class I HDAC inhibitor are selectivity and appropriate pharmacokinetics. The PROTAC technique (Proteolysis Targeting Chimera) is a new method in drug development for the production of active substances that can degrade a protein of interest (POI) instead of inhibiting it.
View Article and Find Full Text PDFImpact of HDAC inhibitors on macrophage polarization to enhance innate immunity against infections.
Drug Discov Today
November 2024
Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands. Electronic address:
Innate immunity plays an important role in host defense against pathogenic infections. It involves macrophage polarization into either the pro-inflammatory M1 or the anti-inflammatory M2 phenotype, influencing immune stimulation or suppression, respectively. Epigenetic changes during immune reactions contribute to long-term innate immunity imprinting on macrophage polarization.
View Article and Find Full Text PDFCharacterization of a novel HDAC2 pathogenetic variant: a missing puzzle piece for chromatinopathies.
Hum Genet
June 2024
Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
Article Synopsis
- Histone deacetylases (HDACs) are crucial for modifying histones, influencing gene expression and chromatin structure, with Class I HDACs being widely expressed and involved in protein complexes.
- A study identified a novel mutation in the HDAC2 gene in a patient with Rubinstein-Taybi syndrome (RSTS), who initially tested negative for known RSTS mutations, suggesting a connection between this mutation and chromatinopathies.
- Investigations revealed that the HDAC2 mutation caused improper localization in the nucleus, altered protein levels, and distinct patterns of gene expression, highlighting HDAC2's potential role in chromatin-related disorders.
First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease.
ACS Chem Neurosci
June 2024
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3β (GSK-3β).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!