Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo

Faraco, Giuseppe; Pittelli, Maria; Cavone, Leonardo; Fossati, Silvia; Porcu, Marco; Mascagni, Paolo; Fossati, Gianluca; Moroni, Flavio; Chiarugi, Alberto

doi:10.1016/j.nbd.2009.07.019

Cited by 122 publications

(87 citation statements)

References 54 publications

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“…This could cause transcriptional activation or inhibition, depending on whether transcription factor(s) or repressor(s) is recruited to the gene promoter. The NF-kB is a substrate of HDACs, and its hyperacetylation by HDAC inhibition causes a loss of NF-kB transactivation (Faraco et al, 2009). Consistent with these reports, we found that both VPA and SB significantly inhibited MCAO-induced NF-kB activation.…”

Section: Discussionsupporting

confidence: 91%

Valproic Acid Attenuates Blood–Brain Barrier Disruption in a Rat Model of Transient Focal Cerebral Ischemia: The Roles of HDAC and MMP-9 Inhibition

Wang

Leng

Tsai

et al. 2010

J Cereb Blood Flow Metab

207

179

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Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is known to protect against cerebral ischemia. The effects of VPA on blood-brain barrier (BBB) disruption were investigated in rats subjected to transient middle cerebral artery occlusion (MCAO). Postischemic VPA treatment remarkably attenuated MCAO-induced BBB disruption and brain edema. Meanwhile, VPA significantly reduced MCAO-induced elevation of matrix metalloproteinase-9 (MMP-9), degradation of tight junction proteins, and nuclear translocation of nuclear factor-jB (NF-jB). Sodium butyrate, another HDAC inhibitor, mimicked these effects of VPA. Our findings suggest that BBB protection by VPA involves HDAC inhibition-mediated suppression of NF-jB activation, MMP-9 induction, and tight junction degradation.

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Section: Discussionsupporting

confidence: 91%

Valproic Acid Attenuates Blood–Brain Barrier Disruption in a Rat Model of Transient Focal Cerebral Ischemia: The Roles of HDAC and MMP-9 Inhibition

Wang

Leng

Tsai

et al. 2010

J Cereb Blood Flow Metab

207

179

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“…The low abundance of class IIa KDACs in the beta cell, described in this study, further supports this notion. The transcription factor NFκB is a central mediator of cytokine signalling in the beta cell [13] and KDAC inhibitors reduce cytokine-induced NFκB-dependent inhibitor protein kappa beta alpha and iNOS production at the protein level in beta [12,25] and in nonbeta cells [45,46], suggesting that deactivation of NFκB is a crucial step in the mechanism of KDAC inhibition of cytokine signalling in beta cells.…”

Section: Discussionmentioning

confidence: 99%

Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

et al. 2010

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Aims/hypothesis Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated. Methods The beta cell line INS-1 and intact rat and human islets were exposed to cytokines with or without ITF2357.Expression of mRNA was assessed by real-time PCR and selected targets validated at the protein level by immunoblotting. Effects on cytokine-induced toxicity were investigated by in vitro assays. Results Hdac1 to Hdac11 were expressed and differentially regulated by cytokines in INS-1 cells and rat islets. HDAC1, -2, -6 and -11 were found to be expressed and regulated by cytokines in human islets. ITF2357 protected against cytokine-induced beta cell apoptosis and counteracted cytokine-induced attenuation of basal insulin secretion. In addition, cytokine-induced regulation of Hdac2 and Hdac6, but not Hdac1 and Hdac11, was reduced by KDAC inhibition. Conclusions/interpretation All classical KDAC genes are expressed by beta cells and differentially regulated by L.G. Grunnet and T. Mandrup-Poulsen contributed equally to this work.Electronic supplementary material The online version of this article

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“…This altered homeostasis ultimately leads to polyclonal hypergammaglobulinemia. Recent studies have shown the HDACi ITF2357 inhibits IL-6 receptor signaling (88) and inflammation in colitis (89) and traumatic brain injury (90) by decreasing inflammatory mediator production triggered by glial cell activation (91). IL-6 receptor inhibition currently is being pursued in clinical trials as a means to ameliorate SLE (92), possibly through the inhibition of plasmacytoid dendritic cells (93).…”

Section: Lupus Models For Hdac Inhibitionmentioning

confidence: 99%

HDAC Inhibition in Lupus Models

Reilly

Regna

Mishra

2011

Mol Med

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Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo

Cited by 122 publications

References 54 publications

Valproic Acid Attenuates Blood–Brain Barrier Disruption in a Rat Model of Transient Focal Cerebral Ischemia: The Roles of HDAC and MMP-9 Inhibition

Valproic Acid Attenuates Blood–Brain Barrier Disruption in a Rat Model of Transient Focal Cerebral Ischemia: The Roles of HDAC and MMP-9 Inhibition

Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

HDAC Inhibition in Lupus Models

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