High doses of the histone deacetylase inhibitor sodium butyrate trigger a stress-like response

The hypothalamic–pituitary–adrenal (HPA) axis is activated by a wide range of stimuli, including drugs. Here we report that in male rats, a dose of sodium butyrate (NaBu) that is typically used to inhibit histone deacetylation (1200 mg/kg) increased the peripheral levels of HPA hormones and glucose....

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Bibliographic Details
Published in:Neuropharmacology 2014-04, Vol.79, p.75-82
Main Authors: Gagliano, Humberto, Delgado-Morales, Raul, Sanz-Garcia, Ancor, Armario, Antonio
Format: Article
Language:English
Subjects:
Acetylation
Adrenocorticotropic Hormone - blood
Animals
Blood Glucose - drug effects
Brain - drug effects
Brain - physiopathology
Butyric Acid - administration & dosage
Butyric Acid - adverse effects
Corticosterone - blood
Dose-Response Relationship, Drug
Hippocampus - drug effects
Hippocampus - physiopathology
Histone Deacetylase Inhibitors - administration & dosage
Histone Deacetylase Inhibitors - adverse effects
Histones - metabolism
Hypothalamic–pituitary–adrenal axis
Hypothalamus - drug effects
Hypothalamus - physiopathology
Male
Mice, Inbred A
Proto-Oncogene Proteins c-fos - metabolism
PVN
Rats
Rats, Sprague-Dawley
Sodium - blood
Sodium butyrate
Stress
Stress, Physiological - drug effects
Stress, Physiological - physiology
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Summary:The hypothalamic–pituitary–adrenal (HPA) axis is activated by a wide range of stimuli, including drugs. Here we report that in male rats, a dose of sodium butyrate (NaBu) that is typically used to inhibit histone deacetylation (1200 mg/kg) increased the peripheral levels of HPA hormones and glucose. In a further experiment, we compared the effects of two different doses of NaBu (200 and 1200 mg/kg) and equimolar saline solutions on peripheral neuroendocrine markers and brain c-Fos expression to demonstrate a specific stress-like effect of NaBu that is not related to hypertonicity and to localise putatively involved brain areas. Only the high dose of NaBu increased the plasma levels of stress markers. The equimolar (hypertonic) saline solution also activated the HPA axis and the c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN), a key area for the control of the HPA axis, but the effects were of a lower magnitude than those of NaBu. Regarding other brain areas, group differences in c-Fos expression were not observed in the medial prefrontal cortex or the medial amygdala, but they were observed in the central amygdala and the lateral ventral septum. However, only the latter area of the NaBu group showed enhanced c-Fos expression that was significantly higher than that after hypertonic saline. The present data indicate that high doses of NaBu appear to act as a pharmacological stressor, and this fact should be taken into account when using this drug to study the role of epigenetic processes in learning and emotional behaviour. •Sodium butyrate (NaBu) activates the hypothalamus–pituitary–adrenal (HPA) axis.•NaBu-induced HPA activation is not explained by hypertonicity.•NaBu selectively induced c-Fos expression in the lateral septum-ventral part.•Stressful properties of NaBu may explain certain effects of the drug.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2013.10.031