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Neuronal apoptosis induced by histone deacetylase inhibitors
A Salminen1, T Tapiola, P Korhonen
1Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland. antero.salminen@uku.fi
Abstract:
Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 microM TSA and 1-10 mM butyrate for 1-2 days. Both of these inhibitors induced a prominent neuronal apoptosis characterized by morphological changes as well as by the activation of caspase-3 protease and subsequent cleavage of poly(ADP-ribose) polymerase, one of the caspase-3 targets. Caspase-3 activities reached the highest level on the second day after treatment, higher in the proliferating neuroblastoma cells than in the cerebellar granule neurons. Caspase-3 activation and morphological changes were prevented by cycloheximide treatment. Histone deacetylase inhibitors increased the DNA-binding activities of AP1, CREB and NF-kappaB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells.
Insights
High levels of histone acetylation from inhibitors like trichostatin A induced neuronal apoptosis. This stress response involved caspase-3 activation and increased transcription factor activity in neurons.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Histone acetylation regulates gene transcription, impacting neuronal functions.
- Gene repression is implicated in neurodegenerative diseases and aging.
- Histone deacetylase (HDAC) inhibitors are potential therapeutic agents.
Purpose of the Study:
- To investigate the effects of HDAC inhibitors, trichostatin A (TSA) and sodium butyrate, on neuronal cell metabolism.
- To determine the impact of excessive histone acetylation on neuronal cell viability and function.
Main Methods:
- Cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells were treated with TSA and sodium butyrate.
- Apoptosis was assessed via morphological changes and caspase-3 activity.
- DNA-binding activities of transcription factors AP1, CREB, and NF-kappaB were measured.
Main Results:
- HDAC inhibitors induced significant neuronal apoptosis, marked by caspase-3 activation and poly(ADP-ribose) polymerase cleavage.
- Caspase-3 activation peaked on day two, with higher levels in neuroblastoma cells.
- HDAC inhibition increased DNA-binding activities of AP1, CREB, and NF-kappaB.
- Cycloheximide prevented TSA- and butyrate-induced apoptosis and morphological changes.
Conclusions:
- Excessive histone acetylation triggers a cellular stress response leading to apoptotic cell death in neuronal cells.
- HDAC inhibitors can induce neuronal apoptosis, suggesting a delicate balance in histone acetylation levels.
- Understanding these mechanisms is crucial for developing treatments for neurodegenerative conditions.