Histone Deacetylase Activity Levels Research Articles

The Effects of Histone Deacetylase Inhibition on the Levels of Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine

Studies have suggested the involvement of inflammatory processes in the physiopathology of bipolar disorder. Preclinical evidences have shown that histone deacetylase inhibitors may act as mood-stabilizing agents and protect the brain in models of mania and depression. The aim of the present study was to evaluate the effects of sodium butyrate (SB) and valproate (VPA) on behavioral changes, histone deacetylase activity, and the levels of cytokines in an animal model of mania induced by dextroamphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for a period of 14days, and then, between the 8th and 14th days, the rats were treated with SB, VPA, or Sal. The activity of histone deacetylase and the levels of cytokines (interleukin (IL) IL-4, IL-6, and IL-10 and tumor necrosis factor-alpha (TNF-α)) were evaluated in the frontal cortex and striatum of the rats. The administration of d-AMPH increased the activity of histone deacetylase in the frontal cortex. Administration of SB or VPA decreased the levels of histone deacetylase activity in the frontal cortex and striatum of rats. SB per se increased the levels of cytokines in both of the brain structures evaluated. AMPH increased the levels of cytokines in both of the brain structures evaluated, and VPA reversed this alteration. The effects of SB on d-AMPH-induced cytokine alterations were dependent on the brain structure and the cytokine evaluated. Despite VPA and SB having a similar mechanism of action, both being histone deacetylase inhibitors, they showed different effects on the levels of cytokines. The present study reinforces the need for more research into histone deacetylase inhibitors being used as a possible target for new medications in the treatment of bipolar disorder.

Abstract 1325: Oral delivery of drug-loaded microspheres for cancer

Abstract The oral route remains the preferred method of administering drugs; however, this delivery mode faces many challenges, including low bioavailability of the administered drug, generalized toxicity and drug decomposition. Microsphere drug delivery systems have evolved to improve patient compliance, reduce toxicity, and increase efficacy. Additionally, the use of microspheres to deliver drugs has many other advantages, such as control-release of the active drug, increase bioavailability and target delivery of the drug to the desired tissue/cell. Our research explored the utility of encapsulating vorinostat in biodegradable microsphere delivery system, to be delivered orally via a capsule, to attain effective therapeutic effect. The strategy is to develop an oral, biodegradable albumin-based microsphere delivery system containing vorinostat that would elicit targeted inhibitory effect on cancer to enhance therapeutic efficacy. Vorinostat-loaded microspheres were prepared by a microencapsulation method through spray drying. The parameters for spray drying were optimized to find the best formulation for enhanced uptake and efficacy in vitro in cultured HEPG2 cells. Microspheres were loaded into capsules. Microspheres and capsule formulations were assessed for particle size, particle size distribution, surface morphology and properties and Zeta potential measurements. Drug release characteristics were quantified using dissolution studies. Chemical and thermal stability of the encapsulated drug and microsphere formulations were evaluated using FTIR and DSC, respectively. The uptake and cellular internalization of the microspheres were evaluated using co-cultures of Caco-2 cells and Raji cells. In vitro cytotoxicity was evaluated using MTT and clonogenic assays. Histone deacetylase (HDAC) activity levels in cells from treatment of free vorinostat and microparticle formulation were compared. Global histone modifications in HEPG2 cancer cells due to vorinostat-loaded microsphere treatment were also analyzed. Our data indicated that vorinostat microspheres were 1-2 microns in size and possessed spherical morphology. Zeta potential measurements show values of -30 mV, which indicated colloidal stability of the microsphere dispersion. Uptake studies indicated that more than 50% of the microspheres were internalized inside the cells within 12 hours. Additionally, dissolution studies showed that within 24 hours, 80% of the drug is sustained-release from the microsphere formulations. HDAC activity levels were shown to be decreased in cultured cells when vorinostat microspheres were used. Our in vitro studies showed that drug-loaded microsphere formulations exert cytotoxic effects on cultured cells. In summary, microspheres were shown to be a potential effective oral delivery system to administer anticancer drugs, with enhanced efficacy due to their controlled-release manner. Citation Format: Duc P. Do. Oral delivery of drug-loaded microspheres for cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1325.

Histone deacetylase inhibition with trichostatin A does not reverse severe angioproliferative pulmonary hypertension in rats (2013 Grover Conference series).

Pulmonary arterial hypertension (PAH) is a rapidly progressive and devastating disease characterized by remodeling of lung vessels, increased pulmonary vascular resistance, and eventually right ventricular hypertrophy and failure. Because histone deacetylase (HDAC) inhibitors are agents hampering tumor growth and cardiac hypertrophy, they have been attributed a therapeutic potential for patients with PAH. Outcomes of studies evaluating the use of HDAC inhibitors in models of PAH and right ventricular pressure overload have been equivocal, however. Here we describe the levels of HDAC activity in the lungs and hearts of rats with pulmonary hypertension and right heart hypertrophy or failure, experimentally induced by monocrotaline (MCT), the combined exposure to the VEGF-R inhibitor SU5416 and hypoxia (SuHx), and pulmonary artery banding (PAB). We show that HDAC activity levels are reduced in the lungs of rat with experimentally induced hypertension, whereas activity levels are increased in the hypertrophic hearts. In contrast to what was previously found in the MCT model, the HDAC inhibitor trichostatin A had no effect on pulmonary vascular remodeling in the SuHx model. When our results and those in the published literature are taken together, it is suggested that the effects of HDAC inhibitors in humans with PAH and associated RV failure are, at best, unpredictable. Significant progress can perhaps be made by using more specific HDAC inhibitors, but before clinical tests in human PAH can be undertaken, careful preclinical studies are required to determine potential cardiotoxicity.