Neuroanatomical Profile of Antimaniac Effects of Histone Deacetylases Inhibitors

Abstract

An increasing number of studies have evaluated the potential therapeutic relevance of histone deacetylases (HDAC) inhibitors in mood disorder including bipolar disorder (BD). It has been suggested that the anterior limbic, which controls impulsivity and psychosis, is dysfunctional in BD. The present studies aims to evaluate the effects of microinjection of HDAC inhibitors in the ventricle, amygdala, striatum, prefrontal, and hippocampus on m-amphetamine-induced manic-like behavior in rats. Rats were given a single intracerebral (in the ventricle, amygdala, striatum, prefrontal, or hippocampus) injection of artificial cerebrospinal fluid, sodium butyrate (SB), or valproate (VPA) followed by an intraperitoneal injection of saline or m-AMPH 2 h before the open-field task. The activity of HDAC was evaluated in amygdala, striatum, prefrontal, and hippocampus of animals. The microinjection of SB and VPA in the ventricle, amygdala, striatum, and prefrontal, but not in hippocampus blocked the hyperactivity induced by m-AMPH. In addition, SB and VPA inhibited the HDAC activity; however, this effect varied depending on the experimental procedure and the brain structure evaluated. Our results suggest that the antimanic effects of SB and VPA, HDAC inhibitors, are related to the amygdala, striatum, and prefrontal, but not the hippocampus. More studies are needed to clarify the therapeutic effects of the HDAC inhibitor in BD and thereby develop new drugs.

Histone deacetylase activity and brain-derived neurotrophic factor (BDNF) levels in a pharmacological model of mania

“…38 Therefore, the finding that AMPH-induced hyperlocomotion is partially blocked by SB treatment, as well as by Li and VPT treatment, suggests that SB may have mood-stabilizing properties. 18,29 Based on this pre-established relevance of the AMPH treatment as a valid animal model of mania, we are able to suggest that the results found in our experiments can be of relevance for human patients with BD. Nevertheless, clear extrapolations to the human condition regarding the doses of the tested drugs are less likely to be made, mostly due to differences in the metabolism of rats and humans and, therefore, in the kinetics of the drugs.…”

“…More recently, Arent et al showed different effects of SB treatment in specific brain regions, suggesting that the antimanic effects of SB and of VPT are related to the amygdala, striatum, and, of special interest here, to the PFC, although not to the hippocampus. 29 More studies are warranted to clarify the effects of these HDAC inhibitors in different brain regions. Of note, the lack of between-group differences in HDAC activity in PBMCs in our sample suggests that the modulation of HDAC activity by the tested drugs is mainly central and cannot be observed in the periphery.…”

Sodium Butyrate Prevents Memory Impairment by Re-establishing BDNF and GDNF Expression in Experimental Pneumococcal Meningitis

“…or saline [17]. Eighteen hours after induction, all animals received ceftriaxone (100-mg/kg body weight given s.c./7 days) [18].…”

Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats

“…It has been shown that VPA modulates the epigenetic programming by inhibiting histone deacetylases (HDAC) (Machado-Vieira et al, 2011). Recent preclinical studies from our research group showed that treatment with sodium butyrate (SB), an inhibitor of histone deacetylase like VPA, was able to reverse the manic-like behavior induced by amphetamine in rodents (Arent et al, 2011;Resende et al, 2013;Steckert et al, 2013;Valvassori et al, 2013).…”