Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons

Int J Neuropsychopharmacol. 2008 Dec;11(8):1123-34. doi: 10.1017/S1461145708009024. Epub 2008 Jul 9.


Parkinson's disease (PD) is characterized by the selective and progressive loss of dopaminergic (DA) neurons in the midbrain substantia nigra. Currently, available treatment is unable to alter PD progression. Previously, we demonstrated that valproic acid (VPA), a mood stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, increases the expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in astrocytes to protect DA neurons in midbrain neuron-glia cultures. The present study investigated whether these effects are due to HDAC inhibition and histone acetylation. Here, we show that two additional HDAC inhibitors, sodium butyrate (SB) and trichostatin A (TSA), mimic the survival-promoting and protective effects of VPA on DA neurons in neuron-glia cultures. Similar to VPA, both SB and TSA increased GDNF and BDNF transcripts in astrocytes in a time-dependent manner. Furthermore, marked increases in GDNF promoter activity and promoter-associated histone H3 acetylation were noted in astrocytes treated with all three compounds, where the time-course for acetylation was similar to that for gene transcription. Taken together, our results indicate that HDAC inhibitors up-regulate GDNF and BDNF expression in astrocytes and protect DA neurons, at least in part, through HDAC inhibition. This study indicates that astrocytes may be a critical neuroprotective mechanism of HDAC inhibitors, revealing a novel target for the treatment of psychiatric and neurodegenerative diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Brain Neoplasms / metabolism
  • Brain-Derived Neurotrophic Factor / biosynthesis*
  • Brain-Derived Neurotrophic Factor / genetics
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Dopamine / physiology*
  • Dopamine Uptake Inhibitors / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Female
  • GABA Agents / pharmacology
  • Glial Cell Line-Derived Neurotrophic Factor / biosynthesis*
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glioma / metabolism
  • Histone Deacetylase Inhibitors*
  • Immunohistochemistry
  • Immunoprecipitation
  • Mesencephalon / cytology
  • Mesencephalon / drug effects
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neurons / drug effects
  • Neurons / physiology*
  • Neuroprotective Agents*
  • Pregnancy
  • RNA / biosynthesis
  • RNA / genetics
  • Rats
  • Rats, Inbred F344
  • Transcription, Genetic / drug effects
  • Valproic Acid / pharmacology


  • Brain-Derived Neurotrophic Factor
  • Dopamine Uptake Inhibitors
  • Enzyme Inhibitors
  • GABA Agents
  • Glial Cell Line-Derived Neurotrophic Factor
  • Histone Deacetylase Inhibitors
  • Neuroprotective Agents
  • Valproic Acid
  • RNA
  • Dopamine