The International Journal of Neuropsychopharmacology

Research Article

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

Xuefei Wua1a4, Po See Chena1a5, Shannon Dallasa1, Belinda Wilsona1, Michelle L. Blocka1a8, Chao-Chuan Wanga1a6, Harriet Kinyamua2, Nick Lua3, Xi Gaoa1a4, Yan Lenga7, De-Maw Chuanga7, Wanqin Zhanga4, Ru Band Lua5 and Jau-Shyong Honga1 c1

a1 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

a2 Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

a3 Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

a4 Department of Physiology, Dalian Medical University, Dalian, China

a5 Institute of Basic Medical Sciences and Department of Psychiatry, Medical College and Hospital, National Cheng Kung University, Tainan, Taiwan

a6 Department of Anatomy, College of Medicine, Kaohsiung Medical University, Taiwan

a7 Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

a8 Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA, USA

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.

(Received October 17 2007)

(Reviewed December 23 2007)

(Revised April 21 2008)

(Accepted May 14 2008)

(Online publication July 09 2008)

Correspondence:

c1 Address for correspondence: J.-S. Hong, Ph.D., Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Tel.: (919) 541-2358 Fax: (919)541-0841 E-mail: hong3@niehs.nih.gov.