Histone deacetylases (HDACs) and brain function

Volmar, Claude‐Henry; Wahlestedt, Claes

doi:10.1016/j.nepig.2014.10.002

Cited by 127 publications

(84 citation statements)

References 109 publications

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“…They constitute the primary active immune defense in the central nervous system and are constantly scavenging for plaques, damaged neurons, and infectious agents [Estes and McAllister, 2015;Mhatre et al, 2015;Matt and Johnson, 2016]. Butyrate is the most potent of the SCFA HDACi Wagner et al, 2013;Natarajan and Pluznick, 2014], and its potential use in the intervention of neurodegenerative diseases and psychiatric disorders is of longstanding interest [Chuang et al, 2009;Thomas, 2009;Grayson et al, 2010;Canani et al, 2012;Harrison and Dexter, 2013;Rosenstock, 2013;De Vadder et al, 2014;Sezgin and Dincer, 2014;Szyf, 2015;Volmar and Wahlestedt, 2015;Moos et al, 2016].…”

Section: Apoptotic Priming In Mitochondriamentioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Apoptotic Priming In Mitochondriamentioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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“…‘Decreased prepulse inhibition', an important phenotype in SZ patients and animal models, and decreased GAD1 transcripts caused by overexpression of HDAC1 in adult mouse hippocampus confirm the finding that histone acetylation is associated with GABAergic neurotransmission and SZ phenotype [76,77]. Unsurprisingly, there are studies focusing on HDAC inhibitors, reversing the effect of HDAC1 increased expression, in various neurological disorders [77].…”

Section: Epigenetic Regulations Of Gabaergic Neurotransmission In Neumentioning

confidence: 72%

“…Additionally, histone acetylation and deacetylation, with opposing effects, are histone modification marks (writers and erasers) that have been associated with regulation of GABAergic gene expression in SZ and other bipolar disorder [76]. These epigenetic marks have been associated with brain development - brain structural integration as well as memory and cognitive functions and are deregulated in multiple neurological disorders [76,77]. Histone acetylation, like H3K4 methylation, positively mediates GAD1 transcription [76].…”

Section: Gabaergic Gene Regulation - Activating H3k4 Methylation and mentioning

confidence: 99%

“…Unsurprisingly, there are studies focusing on HDAC inhibitors, reversing the effect of HDAC1 increased expression, in various neurological disorders [77]. Studies focusing on various HDAC inhibitors such as valproate and clozapine have shown that they improve cognitive functions and synaptic plasticity in SZ mouse models [77,127]. A study elucidating the mechanism of hyposensitivity to GABAergic neurotransmission during alcohol withdrawal showed that increased levels of HDAC transcripts in the alcohol withdrawal brain slices reduced the level of α 1 -subunit of GABA A receptors.…”

Section: Epigenetic Regulations Of Gabaergic Neurotransmission In Neumentioning

confidence: 99%

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Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

Shrestha

Offer²

2016

Med Epigenet

6,446

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The GABAergic neurotransmission is a highly conserved system that has been attributed to various regulatory events. There has been a notable number of studies on the importance of GABAergic neurotransmission, both excitatory and inhibitory, in neurogenesis and central nervous system development including its control of neuronal cell proliferation and migration, synaptogenesis, dendrite formation and branching, and new neuronal cell integration in the adult brain. There has been remarkable progress in understanding the epigenetic regulations of GABAergic genes and their aberrant expressions in various neurological disorders such as autism spectrum disorder, Rett's syndrome, schizophrenia and PWS. The roles of histone modifications, chromatin looping and gene methylation have been implicated in altered regulations of key genes in the GABAergic pathway. Taken together, they affect the functioning of GABAergic neurotransmission and disrupt various events in brain development. Here, we focus on the role of GABAergic neurotransmission in brain development and on how various genetic and epigenetic events regulate the GABAergic genes in pre- and postnatal brain. We also discuss how these regulatory mechanisms contribute to the pathogenesis of neurological disorders and, therefore, can be used in the development of potential epigenetic therapy for these diseases.

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“…The aliphatic carbon chain can be varied to optimise the pharmacokinetics of these novel HDAC inhibitors. The therapeutic class histone deacetylase inhibitors are central to the design neurological and psychiatric drugs [224]. A series of suberoylanilide hydroxamic acid (SAHA) substituted compounds was synthesised and evaluated for their inhibitory and cytotoxic activity.…”

Section: Histone Deacetylase Inhibitors (Hdac)mentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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Histone deacetylases (HDACs) and brain function

Cited by 127 publications

References 109 publications

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

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