Neuronal apoptosis induced by histone deacetylase inhibitors

• Published in: Brain research. Molecular brain research. 1998-10, Vol.61 (1), p.203-206
• Main Authors: Salminen, Antero, Tapiola, Tero, Korhonen, Pauliina, Suuronen, Tiina
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Cell structures and functions; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - enzymology; Cytoskeleton, cytoplasm. Intracellular movements; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Histone acetylation; Histone Deacetylase Inhibitors; Mice; Molecular and cellular biology; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Rats; Rats, Wistar; Sodium butyrate; Transcription factor; Trichostatin A; Tumor Cells, Cultured
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(98)00210-1

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 μM 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-κB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells.