NEURONAL APOPTOSIS INDUCED BY HISTONE DEACETYLASE INHIBITORS

Histone acetylation has a key role in transcriptional activation, wher eas deacetylation of histones correlates with the transcriptional repr ession and silencing of genes. Genetic repression may have an importan t role in neuronal aging, atrophy and degenerative diseases. Our aim w as to study how histone deacetylase inhibitors, trichostatin A (TSA) a nd sodium butyrate, affect the metabolism of cultured rat cerebellar g ranule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 mu M TSA and 1-10 mM butyrate for 1-2 days. Both o f these inhibitors induced a prominent neuronal apoptosis characterize d by morphological changes as well as by the activation of caspase-3 p rotease 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 neurob lastoma cells than in the cerebellar granule neurons. Caspase-3 activa tion and morphological changes were prevented by cycloheximide treatme nt. Histone deacetylase inhibitors increased the DNA-binding activitie s of AP1, CREB and NF-kappa B transcription factors. These observation s show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells. (C) 1998 Else vier Science B.V. All rights reserved.