Multiple roles of HDAC inhibition in neurodegenerative conditions

Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Drive MSC 1363, Bethesda, MD 20892-1363, USA.
Trends in Neurosciences (Impact Factor: 13.56). 09/2009; 32(11):591-601. DOI: 10.1016/j.tins.2009.06.002
Source: PubMed


Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histones and other proteins and in regulating fundamental cellular activities such as transcription. A wide range of brain disorders are associated with imbalances in protein acetylation levels and transcriptional dysfunctions. Treatment with various HDAC inhibitors can correct these deficiencies and has emerged as a promising new strategy for therapeutic intervention in neurodegenerative disease. Here, we review and discuss intriguing recent developments in the use of HDAC inhibitors to combat neurodegenerative conditions in cellular and disease models. HDAC inhibitors have neuroprotective, neurotrophic and anti-inflammatory properties; improvements in neurological performance, learning/memory and other disease phenotypes are frequently seen in these models. We discuss the targets and mechanisms underlying these effects of HDAC inhibition and comment on the potential for some HDAC inhibitors to prove clinically effective in the treatment of neurodegenerative disorders.

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    • "In humans and rodents, multiple HDAC enzymes have been identified. Based on their homology to yeast histone deacetylases they are divided into four major classes (Chuang et al., 2009). Class I HDACs include HDAC1, 2, 3 and 8. Class II HDACs comprise HDAC4, 5, 6, 7, 9 and 10. "
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    ABSTRACT: A prominent role of epigenetic mechanisms in manifestation of epilepsy has been proposed. Thus altered histone H3 and H4 acetylation has been demonstrated in experimental models of temporal lobe epilepsy (TLE). We now investigated changes in the expression of the class I and class IV histone deacetylases (HDAC) in two complementary mouse TLE models. Unilateral intrahippocampal injection of kainic acid (KA) induced a status epilepticus lasting 6 to 24 h, development of spontaneous limbic seizures (2 to 3 days after KA injection) and chronic epilepsy, as revealed by telemetric recordings of the EEGs. Mice were killed at different intervals after KA injection and expression of HDAC mRNAs was investigated by in situ hybridization. We observed marked decreases in the expression of HDACs 1, 2 and 11 (by up to 75%) in the granule cell and pyramidal cell layers of the hippocampus during the acute status epilepticus (2 to 6 h after KA injection). This was followed by increased expression of all class I HDAC mRNAs in all principal cell layers of the hippocampus after 12 to 48 h. In the chronic phase, 14 and 28 days after KA, only modest increases in the expression of HDAC1 mRNA were observed in granule and pyramidal cells. Immunohistochemistry using an antibody detecting HDAC2 revealed results consistent with the mRNA data and indicates also expression in glial cells on the injection side. Similar changes as seen in the KA model were observed after a pilocarpine-induced status epilepticus except that decreases in HDACs 2, 3 and 8 were also seen at the chronic 28 day interval.
    Experimental Neurology 07/2015; DOI:10.1016/j.expneurol.2015.07.026 · 4.70 Impact Factor
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    • "(1) Class I HDACs consist of HDACs 1, 2, 3, 8; (2) Class II HDACs further separate into two subclasses, class IIa including HDACs 4, 5, 7, 9 and class IIb HDACs 6, 10; (3) Class III HDACs are named as sirtuins and include SirT1-7, sharing their homology sequence to the yeast Sir2; and (4) Class IV HDACs include only HDAC11 (Chuang et al., 2009 "
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    ABSTRACT: It is becoming more evident that histone acetylation, as one of the epigenetic modifications or markers, plays a key role in the etiology of Alzheimer's disease (AD). Histone acetylases and histone deacetylases (HDACs) are the well-known covalent enzymes that modify the reversible acetylation of lysine residues in histone amino-terminal domains. In AD, however, the roles of these enzymes are controversial. Some recent studies indicate that HDAC inhibitors are neuroprotective by regulating memory and synaptic dysfunctions in cellular and animal models of AD; while on the other hand, increase of histone acetylation have been implicated in AD pathology. In this review, we focus on the recent advances on the roles of histone acetylation covalent enzymes in AD and discuss how targeting these enzymes can ultimately lead to therapeutic approaches for treating AD.
    Frontiers in Cellular Neuroscience 06/2015; 9:226. DOI:10.3389/fncel.2015.00226 · 4.29 Impact Factor
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    • "Therefore , it is not surprising that a number of studies have been investigating the trainability of working memory across the lifespan (Takeuchi et al. 2010; Morrison and Chein 2011; Shipstead et al. 2010). SIRT1 activators (e.g., resveratrol) have emerged as a promising new treatment for age-related brain disorders since it has been reported to play a relevant role promoting learning (Chuang et al. 2009; Gao et al. 2010). Thus, the aim of this study was to examine the effects of chronic resveratrol administration in old rats on in vivo synthesis and metabolism of monoamines (5-HT, NA, and DA) in crucial brain regions for regulation of memory processing, in parallel to behavioral performance evaluation on working memory test. "
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    ABSTRACT: Resveratrol is a polyphenol exhibiting antioxidant and neuroprotective effects in neurodegenerative diseases. However, neuroprotective properties during normal aging have not been clearly demonstrated. We analyzed the in vivo effects of chronic administration of resveratrol (20 mg/kg/day for 4 weeks) in old male rats (Wistar, 20 months), on tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities which mediate central monoaminergic neurotransmitters synthesis, and besides, on hippocampal-dependent working memory test (radial maze). Our results show an age-related decline in neurochemical parameters that were reversed by resveratrol administration. The resveratrol treatment enhances serotonin (5-HT) levels in pineal gland, in hippocampus, and in striatum, and those of noradrenaline (NA) in hippocampus and also dopamine (DA) in striatum. These changes were largely due to an increased activity of TPH-1 (463 % in pineal gland), TPH-2 (70-51 % in hippocampus and striatum), and TH (150-36 % in hippocampus and striatum). Additionally, the observed hippocampal effects correlate with a resveratrol-induced restorative effect on working memory (radial maze). In conclusion, this study suggests resveratrol treatment as a restoring therapy for the impaired cognitive functions occurring along normal aging process, by preventing 5-HT, DA, and NA neurotransmission decline.
    Age 06/2015; 37(3):9777. DOI:10.1007/s11357-015-9777-x · 3.45 Impact Factor
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