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HDAC inhibitors and neurodegeneration: at the edge between protection and damage

Karen C Dietz1, Patrizia Casaccia

  • 1Department of Neuroscience and Genetics & Genomics, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1065, New York, NY 10029, United States.

Pharmacological Research
|February 4, 2010
PubMed

Insights

Histone deacetylase inhibitors (HDACIs) show varied effects in neurodegenerative disorders. Understanding their impact on different cell types and specific HDAC isoforms is key to optimizing their therapeutic potential.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Histone deacetylase inhibitors (HDACIs) are investigated for treating neurodegenerative disorders.
  • Observed therapeutic effects of broad-spectrum HDACIs are inconsistent, ranging from protective to detrimental.
  • This heterogeneity necessitates a deeper understanding of HDACI mechanisms.

Purpose of the Study:

  • To review the underlying causes for the contradictory functional responses to HDACIs in neurodegenerative disorders.
  • To explore the role of differential gene expression and non-histone targets in HDACI outcomes.
  • To emphasize the importance of cell-type-specific effects and isoform contributions.

Main Methods:

  • Review of existing literature on HDACIs in neurodegenerative disease models.
  • Analysis of gene expression changes induced by HDACIs.
  • Discussion of HDAC isoform-specific functions and non-histone substrates.

Main Results:

  • HDACIs can lead to both pro-apoptotic and anti-apoptotic gene expression, depending on the cell type.
  • Broad-spectrum HDACIs may affect nuclear and cytosolic HDAC isoforms with diverse non-histone substrates.
  • Conflicting outcomes may arise from differential HDACI effects on neuronal, glial, and inflammatory cells.

Conclusions:

  • The therapeutic efficacy of HDACIs is influenced by their impact on distinct cell types within the central nervous system.
  • Targeting specific HDAC isoforms or considering cell-specific responses may improve HDACI-based therapies.
  • Further research is needed to elucidate the complex interplay of HDACs in neurodegeneration for effective treatment strategies.

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