Histone deacetylase inhibition is cytotoxic to oligodendrocyte precursor cells in vitro and in vivo

Abstract

Histone deacetylase (HDAC) inhibition mediated by small molecule HDAC inhibitors (HDACi) has demonstrated divergent effects including toxicity towards transformed cell lines, neuroprotection in neurological disease models, and inhibition of oligodendrocyte precursor cell (OPC) differentiation to mature oligodendrocytes (OL). However, it remains unknown if transient HDAC inhibition may promote OPC survival. Using mouse cortical OPC primary cultures, we investigated the effects of the FDA approved pan-HDACi suberoylanilide hydroxamic acid (SAHA) on OPC survival. Initial studies showed differences in the HDAC expression pattern of multiple HDAC isoforms in OPCs relative to their terminally differentiated progeny cells, OLs and astrocytes. Treatment of OPCs with SAHA for up to 72h using a maximum concentration either at or lower than those necessary for cytotoxicity in most transformed cell lines resulted in over 67% reduction in viability relative to vehicle-treated OPCs. This was at least partly due to increased apoptosis as SAHA-treated cells displayed activated caspase 3 and were protected by the general caspase inhibitor Q-VD-OPH. Additionally, SAHA treatment of whole mice at postnatal day 5 induced apoptosis of cortical OPCs. These results suggest that SAHA negatively impacts OPC survival and may be detrimental to the myelinating brain and spinal cord. Such toxicity may be relevant in a clinical context as SAHA is currently involved in numerous clinical trials and is in consideration for use in the treatment of psychiatric and neurodegenerative conditions.

The Differentiation of Rat Oligodendroglial Cells Is Highly Influenced by the Oxygen Tension: In Vitro Model Mimicking Physiologically Normoxic Conditions

“…Interestingly, although strongly influenced by the environmental clues, oligodendrocytes are able to complete their differentiation process both in vitro and in vivo in the absence of neurons to be myelinated [ 40 , 41 ]. This ability of oligodendrocytes to terminally maturate even when maintained as monocultures, enables their use as in vitro models for various applications, like, for instance, testing drugs and neurotoxicants, or disease modelling [ 42 , 43 , 44 , 45 ].…”

Epigenetic regulation of myelination in health and disease

“…Moreover, the application of sodium butyrate (SB, another histone deacetylase inhibitor) was reported to protect against hypoxia-ischemia-induced loss of neuroblasts and OPCs (Ziemka-Nalecz et al, 2017). On the contrary, SAHA (suberoylanilide hydroxamic acid, a pan-HDACi) negatively impacts OPC survival and may be detrimental to the myelinating brain and spinal cord (Dincman et al, 2016), challenging its potential applications in the treatment of psychiatric and neurodegenerative conditions (Baltan, Murphy, Danilov, Bachleda, & Morrison, 2011;Liu et al, 2012;Lv, Han, Sun, Wang, & Dong, 2012;Lv et al, 2011).…”

The role of nitrous oxide in stroke

“… 30 31 However, many studies demonstrate that nitrous oxide at 75 vol% and xenon at 50 vol% can reduce cortical brain damages in vivo , and decrease NMDA-evoked Ca 2+ influxes of neuronal cell, which is a process which is considered as a major primary event involved in the excitotoxic neuronal death. 32 The neuroprotective action of nitrous oxide at 75 vol% and of xenon at 50 vol% after middle cerebral artery occlusion (MCAO) in vivo may account for their pharmacologically antagonistic properties at the NMDA receptor, 33 because the gas have no effect to the α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor. 17 So many dates of studies have shown that nitrous oxide and xenon keep normal cells from excitotoxic neuronal death produced by stimulating either glutamate or NMDA in cortical cell cultures.…”