PMID- 18611290 OWN - NLM STAT- MEDLINE DCOM- 20090126 LR - 20211028 IS - 1461-1457 (Print) IS - 1469-5111 (Electronic) IS - 1461-1457 (Linking) VI - 11 IP - 8 DP - 2008 Dec TI - Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. PG - 1123-34 LID - 10.1017/S1461145708009024 [doi] 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. FAU - Wu, Xuefei AU - Wu X AD - Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. FAU - Chen, Po See AU - Chen PS FAU - Dallas, Shannon AU - Dallas S FAU - Wilson, Belinda AU - Wilson B FAU - Block, Michelle L AU - Block ML FAU - Wang, Chao-Chuan AU - Wang CC FAU - Kinyamu, Harriet AU - Kinyamu H FAU - Lu, Nick AU - Lu N FAU - Gao, Xi AU - Gao X FAU - Leng, Yan AU - Leng Y FAU - Chuang, De-Maw AU - Chuang DM FAU - Zhang, Wanqin AU - Zhang W FAU - Lu, Ru Band AU - Lu RB FAU - Hong, Jau-Shyong AU - Hong JS LA - eng GR - R00 ES015409/ES/NIEHS NIH HHS/United States GR - R00 ES015409-02/ES/NIEHS NIH HHS/United States GR - Z99 MH999999/ImNIH/Intramural NIH HHS/United States GR - R00ES015409/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20080709 PL - England TA - Int J Neuropsychopharmacol JT - The international journal of neuropsychopharmacology JID - 9815893 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Dopamine Uptake Inhibitors) RN - 0 (Enzyme Inhibitors) RN - 0 (GABA Agents) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Neuroprotective Agents) RN - 614OI1Z5WI (Valproic Acid) RN - 63231-63-0 (RNA) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Astrocytes/drug effects/*metabolism MH - Brain Neoplasms/metabolism MH - Brain-Derived Neurotrophic Factor/*biosynthesis/genetics MH - Cells, Cultured MH - Cerebral Cortex/cytology/drug effects/metabolism MH - Dopamine/*physiology MH - Dopamine Uptake Inhibitors/pharmacology MH - Enzyme Inhibitors/*pharmacology MH - Female MH - GABA Agents/pharmacology MH - Glial Cell Line-Derived Neurotrophic Factor/*biosynthesis/genetics MH - Glioma/metabolism MH - *Histone Deacetylase Inhibitors MH - Immunohistochemistry MH - Immunoprecipitation MH - Mesencephalon/cytology/drug effects MH - Neuroglia/drug effects/metabolism MH - Neurons/drug effects/*physiology MH - *Neuroprotective Agents MH - Pregnancy MH - RNA/biosynthesis/genetics MH - Rats MH - Rats, Inbred F344 MH - Transcription, Genetic/drug effects MH - Valproic Acid/pharmacology PMC - PMC2579941 MID - NIHMS69125 EDAT- 2008/07/10 09:00 MHDA- 2009/01/27 09:00 PMCR- 2009/12/01 CRDT- 2008/07/10 09:00 PHST- 2008/07/10 09:00 [pubmed] PHST- 2009/01/27 09:00 [medline] PHST- 2008/07/10 09:00 [entrez] PHST- 2009/12/01 00:00 [pmc-release] AID - S1461145708009024 [pii] AID - 10.1017/S1461145708009024 [doi] PST - ppublish SO - Int J Neuropsychopharmacol. 2008 Dec;11(8):1123-34. doi: 10.1017/S1461145708009024. Epub 2008 Jul 9.