Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects

Vishwakarma, Santosh; Iyer, L.R.; Muley, Milind M.; Singh, Pankaj Kumar; Shastry, Arun; Saxena, Ambrish; Kulathingal, Jayanarayan; Vijaykanth, G.; Raghul, J.; Rajesh, Navin; Rathinasamy, Suresh; Kachhadia, V. V.; Kilambi, Narasimhan; Rajgopal, Sridharan; Gopalan, Balasubramanian; Narayanan, Shridhar

doi:10.1016/j.intimp.2013.03.016

Cited by 108 publications

(79 citation statements)

References 36 publications

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“…This relative lack of CNS activity upon acute systemic administration was in contrast to the potent effects of tubastatin A observed in neuronal culture and peripheral tissues. This suggests that behavioral and neuroprotective effects of tubastatin A previously reported in in vivo models of neurodegenerative disease (Benner et al, 2012) could be independent of a-tubulin acetylation or result from peripheral actions of the drug, such as the regulation of Foxp3 þ regulatory T cells or other inflammatory mediators, which could indirectly affect neurodegenerative processes in brain (Vishwakarma et al, 2013;Beier et al, 2012).…”

Section: Discussionmentioning

confidence: 83%

Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability

Jochems

Boulden

Lee

et al. 2013

Neuropsychopharmacol

149

150

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HDAC inhibitors have been reported to produce antidepressant and pro-cognitive effects in animal models, however, poor brain bioavailability or lack of isoform selectivity of current probes has limited our understanding of their mode of action. We report the characterization of novel pyrimidine hydroxyl amide small molecule inhibitors of HDAC6, brain bioavailable upon systemic administration. We show that two compounds in this family, ACY-738 and ACY-775, inhibit HDAC6 with low nanomolar potency and a selectivity of 60-to 1500-fold over class I HDACs. In contrast to tubastatin A, a reference HDAC6 inhibitor with similar potency and peripheral activity, but more limited brain bioavailability, ACY-738 and ACY-775 induce dramatic increases in a-tubulin acetylation in brain and stimulate mouse exploratory behaviors in novel, but not familiar environments. Interestingly, despite a lack of detectable effect on histone acetylation, we show that ACY-738 and ACY-775 share the antidepressant-like properties of other HDAC inhibitors, such as SAHA and MS-275, in the tail suspension test and social defeat paradigm. These effects of ACY-738 and ACY-775 are directly attributable to the inhibition of HDAC6 expressed centrally, as they are fully abrogated in mice with a neural-specific loss of function of HDAC6. Furthermore, administered in combination, a behaviorally inactive dose of ACY-738 markedly potentiates the anti-immobility activity of a subactive dose of the selective serotonin reuptake inhibitor citalopram. Our results validate new isoform-selective probes for in vivo pharmacological studies of HDAC6 in the CNS and reinforce the viability of this HDAC isoform as a potential target for antidepressant development.

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Section: Discussionmentioning

confidence: 83%

Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability

Jochems

Boulden

Lee

et al. 2013

Neuropsychopharmacol

149

150

View full text Add to dashboard Cite

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“…Tubastatin A is the most effective HDAC6 inhibitor available so far. Tubastatin A has been reported to reduce stress responses and prolong survival in lethal sepsis models (10, 28, 52-54), and tubastatin A also possesses anti-inflammatory, antirheumatic, and neuroprotective effects (8,11,25,45).…”

mentioning

confidence: 99%

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

Shetty

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…These results further confirmed the effects of HDACs on decreasing inflammatory and oxidative stress responses in HF. Studies have also reported that HDAC inhibitors can reduce inflammation and oxidative stress in in vitro models of inflammatory disease [22] . In addition, this study revealed that MPT0E014 can attenuate increases in TGF-β and SMAD2 or SMAD3 responses to HF.…”

Section: Discussionmentioning

confidence: 99%

Novel Histone Deacetylase Inhibitor Modulates Cardiac Peroxisome Proliferator-Activated Receptors and Inflammatory Cytokines in Heart Failure

et al. 2015

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Background: Heart failure (HF) affects cardiac metabolism and inflammation. Histone deacetylases (HDACs) play a critical role in cardiac pathophysiology. This study investigated whether HDAC inhibition can regulate HF by modifying cardiac inflammation and peroxisome proliferator-activated receptor (PPAR) isoforms. Methods: Echocardiography, electrocardiography, ELISA and Western blot were performed in rats with isoproterenol-induced HF, with and without orally administered MPT0E014 (a novel HDAC inhibitor, 50 mg/kg for 7 consecutive days). Results: The left ventricles (LVs) of HF rats expressed significantly higher levels of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 than the healthy LVs did. HF rats treated with MPT0E014 exhibited improved cardiac fraction shortening with reducing chamber size. The MPT0E014-treated HF LVs exhibited a smaller increase in the expression of interleukin (IL)-6, p22, SMAD2/3, extracellular signal-regulated kinase 1/2, PPAR isoforms and circulatory tumor growth factor-β1 than the untreated HF LVs did. Moreover, MPT0E014-treated HF LVs expressed less fibroblast growth factor receptor than untreated HF LVs did. Conclusions: HDAC inhibition can improve cardiac function and attenuate the effects of HF on cardiac metabolism and inflammation, which might contribute to the beneficial effects of HDAC inhibition in HF.

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Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects

Cited by 108 publications

References 36 publications

Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability

Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

Novel Histone Deacetylase Inhibitor Modulates Cardiac Peroxisome Proliferator-Activated Receptors and Inflammatory Cytokines in Heart Failure

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