Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons.
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.
Wu
Xuefei
X
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
Chen
Po See
PS
Dallas
Shannon
S
Wilson
Belinda
B
Block
Michelle L
ML
Wang
Chao-Chuan
CC
Kinyamu
Harriet
H
Lu
Nick
N
Gao
Xi
X
Leng
Yan
Y
Chuang
De-Maw
DM
Zhang
Wanqin
W
Lu
Ru Band
RB
Hong
Jau-Shyong
JS
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D005910:Glioma / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D014158:Transcription, Genetic / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018682:GABA Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D014635:Valproic Acid; D012313:RNA; D004298:Dopamine