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Work for HDAC Inhibitor
editintroduction to uses in psychiatry/neurology: [ADD INTRO HERE?]
HDIs have a long history of use in psychiatry and neurology as mood stabilzers 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.[1] Enhancement of memory formation is increased in mice given the HDIs sodium butyrate or SAHA, or by genetic knockout of the HDAC2 gene in mice.[2] 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.[3]
2.1.1 Pre Clinical Research - HDACi therapy for the treatment of depression
editRecent 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[1].. Recent studies estimate that even after successive treatments with multiple antidepressants, almost 35% of patients did not achieve remission,[2] 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 histone acetylation, particularly at gene loci which have known connection to behavior and mood regulation. [3][1]. 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 HDAC2 and HDAC5 mRNA compared to controls and patients in remission[3]
HDI effects on gene expression
editVarious HDAC 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.[3] 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)[2] as well as Sodium butyrate[3] 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. [2]
HDI effects on depressive behaviors
editPre-clinical research on the use of HDAC 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 HDAC mRNA, acetylation and gene expression these behavioral tests are compared to controls to determine wether 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.[3][1][2] 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[2] in addition to increased expression of BDNF.[3]
Clinical Potential
edit- possibly some future directions of research involving early-phase clinical trials
- ^ a b c Schroeder, M; Hillemacher, T; Bleich, S; Frieling, H (2012). "The Epigenetic Code in Depression: Implications for Treatment". Translation. 91 (2): 310–314. doi:10.1038/clpt.2011.282. PMID 22205200.
- ^ a b c d e Fuchikami, Manabu; Yamamoto, Shigeto; Morinobu, Shigeru; Okada, Satoshi; Yamawaki, Yosuke; Yamawaki, Shigeto (2016). "The potential use of histone deacetylase inhibitors in the treatment of depression". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 64: 320–324. doi:10.1016/j.pnpbp.2015.03.010. PMID 25818247.
- ^ a b c d e f Machado-Vieira, Rodrigo; Ibrahim, Lobna; Zarate, Jr., Carlos A. (2011). "Histone Deacetylases and Mood Disorders: Epigenetic Programming in Gene-Environment Interactions". CNS Neuroscience & Therapeutics. 17: 699–704. doi:10.1111/j.1755-5949.2010.00203. PMID 20961400.