Psychiatry and neurology HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. The prime example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. In more recent times, HDIs are being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. Enhancement of memory formation is increased in mice given vorinostat, or by genetic knockout of the<unk>  gene in mice. While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice that have a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins. Pre Clinical Research – HDI therapy for the treatment of depression Recent research into the causes of depression has highlighted some possible gene-environment interactions that could explain why after much research, no specific genes or loci which would indicate risk for depression have emerged. Recent studies estimate that even after successive treatments with multiple antidepressants, almost 35% of patients did not achieve remission, suggesting that there could be an epigenetic component to depression that is not being addressed by current pharmacological treatments. Environmental stressors, namely traumatic stress in childhood such as maternal deprivation and early childhood abuse have been studied for their connection to a high risk of depression in adulthood. In animal models, these types of trauma have been shown to have significant effects on<unk>  acetylation, particularly at gene loci which have known connection to behavior and mood regulation. Current research has focused on the use of HDI therapy for depression after studies on depressed patients in the middle of a depressive episode found increased expression of<unk>  and<unk>  mRNA compared to controls and patients in remission. Effects on gene expression Various<unk> inhibitors (HDI) have been studied for their connection to the regulation of mood and behavior, each having different, specific effects on the regulation of various genes. The most commonly studied genes include Brain-derived neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) both of which help regulate neuron growth and health, whose down regulation can be a symptom of depression. Multiple studies have shown that treatment with an HDI helps to up regulate expression of BDNF: valproic acid (commonly used to treat epilepsy and bipolar disorder) as well as sodium butyrate both increased expression of BDNF in animal models of depression. One study which traced GDNF levels in the ventral striatum found increased gene expression upon treatment with SAHA. Effects on depressive behaviors Pre-clinical research on the use of<unk> inhibitors (HDI) for the treatment of depression use rodents to model human depression. The tail suspension test (TST) and the forced swimming test (FST) measure the level of defeat in rodents— usually after treatment with chronic stress— which mirrors symptoms of human depression. Alongside tests for levels of<unk> mRNA, acetylation and gene expression these behavioral tests are compared to controls to determine whether or not treatment with an HDI has been successful in ameliorating symptoms of depression. Studies which used SAHA or MS-275 as their treatment compound found treated animals displayed gene expression profiles similar to those treated with fluoxetine, and displayed similar anti-depressant like behavior. Sodium butyrate is commonly used as a candidate for mood disorder treatment: studies using it both alone and in co-treatment with fluoxetine report subjects with increased performance on both TST and FST in addition to increased expression of BDNF. Cancer treatment Pan-HDAC inhibitors have shown anticancer potential in several in in vitro and in vivo studies, focused on Pancreatic, Esophageal squamous cell carcinoma (ESCC), Multiple myeloma, Prostate carcinoma, Gastric cancer, Leukemia, breast, Liver cancer, ovarian cancer, non-Hodgkin lymphoma and Neuroblastoma. Because of the massive effect of pan-HDAC inhibition, witnessed by the very low dosage concentration used and by the countless biological functions affected, many scientists have focused their attention on combining the less specific<unk>  treatment with other more specific anti-cancer drugs, such as the efficacy of the combination treatment with the pan-HDAC inhibitor LBH589 (panobinostat) and the BET bromodomain JQ1 compound. Inflammatory diseases Trichostatin A (TSA) and others are being investigated as anti-inflammatory agents. HIV/AIDS After the successful initial round of in vitro research in January 2013, the Danish Research Council awarded the research team led by Dr. Ole Søgaard from the Danish Aarhus University Hospital the amount of $2 million to proceed with clinical trials on 15 humans. The goal is for<unk> inhibitors to flush HIV from the reservoirs it builds within the DNA of infected cells, followed by a vaccination to help the immune system to neutralize any replicating virus. One study noted the use of panobinostat, entinostat, romidepsin, and vorinostat specifically for the purpose of reactivating latent HIV in order to diminish the reservoirs. Vorinostat was noted as the least potent of the<unk> inhibitors in this trial. Another study found that romidepsin led to a higher and more sustained level of cell-associated HIV RNA reactivation than vorinostat in latently infected T-cells in vitro and ex vivo. Other diseases *Givinostat (ITF2357) is also under investigation for treatment of polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). HDIs are also being studied as protection of heart muscle in acute myocardial infarction.
Histone deacetylase inhibitor
CDK inhibitor
Growth factor receptor inhibitor
Topoisomerase inhibitor
COX-2 inhibitor
Protein kinase inhibitor
Reuptake inhibitor
MEK inhibitor