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

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.

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

“…cells and other cellular models of midbrain DA neurons in vitro (Chen et al 2006;Chen et al 2007;Collins et al 2015;Gardian et al 2004;Kidd and Schneider 2010;Kidd and Schneider 2011;Kontopoulos et al 2006;Outeiro et al 2007;St Laurent et al 2013;Wu et al 2008;Zhu et al 2014). However, to our knowledge, the present study is the first to show that a selective HAT activator can induce similar neurotrophic effects in the SH-SY5Y neuronal cell line.…”

“…We and others have shown that pan-and class-specific HDAC inhibitors can protect DA neurons (Chen et al 2006;Chen et al 2007;Collins et al 2015;Gardian et al 2004;Kidd and Schneider 2010;Kidd and Schneider 2011;Kontopoulos et al 2006;Outeiro et al 2007;St Laurent et al 2013;Wu et al 2008;Zhu et al 2014) and sympathetic neurons (Collins et al 2015) in experimental models of PD. The potential of this approach for clinical translation is highlighted by an ongoing Phase I clinical trial of the FDA-approved drug Glycerol Phenylbutyrate (a HDAC inhibitor) which is exploring the potential of this drug to increase the removal of α-synuclein from the brain (NCT02046434) (for recent reviews see Harrison and Dexter 2013;Schneider et al 2013;Valor et al 2013).…”

Valproate and Amitriptyline Exert Common and Divergent Influences on Global and Gene Promoter-Specific Chromatin Modifications in Rat Primary Astrocytes

“…Astrocytes represent the majority of cells within the CNS, and modulate synaptic strength by their association with synapses (Schipke and Kettenmann, 2004). In addition, astrocytes support neuronal function, as they produce neurotrophic factors, including BDNF and glial-derived neurotrophic factor, also in response to VPA exposure (Chen et al, 2006;Wu et al, 2008c). We monitored drug-induced global epigenetic changes by measuring histone H3 and H4 acetylation/methylation, as well as by DNA methylation.…”

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

“…These processes were linked to the recruitment of the HAT p300 and to the transcriptional activation of Hsp70 in rat cortical neurons and astrocytes [73]. Similar to VPA, TSA, SAHA and SB enhanced GDNF promoter activity and promoter-associated histone H3 acetylation in astrocyte cell culture indicating that HDAC inhibitors upregulate GDNF and BDNF expression in astrocytes and protect DA neurons [74][75][76]. TSA and other HDAC inhibitors including SB, and Class I HDAC-specific inhibitors, such as MS-275 and apicidin, all mimicked the ability of VPA to induce Hsp70 [73,77,78].…”