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

Xuefei Wu, Po See Chen, Shannon Dallas, Belinda Wilson, Michelle Block, Chao Chuan Wang, Harriet Kinyamu, Nick Lu, Xi Gao, Yan Leng, De Maw Chuang, Wanqin Zhang, Ru Band Lu, Jau Shyong Hong

Research output: Contribution to journalArticle

181 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1123-1134
Number of pages12
JournalInternational Journal of Neuropsychopharmacology
Volume11
Issue number8
DOIs
StatePublished - Dec 2008
Externally publishedYes

Fingerprint

Glial Cell Line-Derived Neurotrophic Factor
Histone Deacetylase Inhibitors
Dopaminergic Neurons
Brain-Derived Neurotrophic Factor
Astrocytes
Up-Regulation
trichostatin A
Valproic Acid
Acetylation
Histone Deacetylases
Butyric Acid
Genes
Mesencephalon
Neuroglia
Histones
Parkinson Disease
Neurons
Substantia Nigra
Neurodegenerative Diseases
Anticonvulsants

Keywords

  • Astrocytes
  • BDNF
  • Dopaminergic neurons
  • GDNF
  • Histone acetylation
  • Neurotrophic

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health

Cite this

Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. / Wu, Xuefei; Chen, Po See; Dallas, Shannon; Wilson, Belinda; Block, Michelle; Wang, Chao Chuan; Kinyamu, Harriet; Lu, Nick; Gao, Xi; Leng, Yan; Chuang, De Maw; Zhang, Wanqin; Lu, Ru Band; Hong, Jau Shyong.

In: International Journal of Neuropsychopharmacology, Vol. 11, No. 8, 12.2008, p. 1123-1134.

Research output: Contribution to journalArticle

Wu, X, Chen, PS, Dallas, S, Wilson, B, Block, M, Wang, CC, Kinyamu, H, Lu, N, Gao, X, Leng, Y, Chuang, DM, Zhang, W, Lu, RB & Hong, JS 2008, 'Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons', International Journal of Neuropsychopharmacology, vol. 11, no. 8, pp. 1123-1134. https://doi.org/10.1017/S1461145708009024
Wu, Xuefei ; Chen, Po See ; Dallas, Shannon ; Wilson, Belinda ; Block, Michelle ; Wang, Chao Chuan ; Kinyamu, Harriet ; Lu, Nick ; Gao, Xi ; Leng, Yan ; Chuang, De Maw ; Zhang, Wanqin ; Lu, Ru Band ; Hong, Jau Shyong. / Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. In: International Journal of Neuropsychopharmacology. 2008 ; Vol. 11, No. 8. pp. 1123-1134.
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AB - 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.

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