scholarly journals Targeting Histone Deacetylases as a Multifaceted Approach to Treat the Diverse Outcomes of Stroke

Stroke ◽  
2009 ◽  
Vol 40 (8) ◽  
pp. 2899-2905 ◽  
Author(s):  
Brett Langley ◽  
Camille Brochier ◽  
Mark A. Rivieccio
Keyword(s):  
Protein Function ◽  
Histone Deacetylases ◽  
Cell Loss ◽  
Focal Ischemia ◽  
Therapeutic Window ◽  
Low Molecular Weight ◽  
Hdac Inhibition ◽  
Preclinical Models ◽  
Multifaceted Approach ◽  
Tissue Plasminogen

Achieving therapeutic efficacy in ischemic stroke represents one of the biggest challenges in translational neurobiology. Despite extensive efforts, tissue plasminogen activator remains the only available intervention for enhancing functional recovery in humans once a stroke has occurred. To expand the repertoire of therapeutic options in stroke, one must consider and target its diverse pathophysiologies that trigger cell loss in a manner that also permits and enhances neuronal plasticity and repair. Several converging lines of inquiry suggest that histone deacetylase (HDAC) inhibition could be a strategy to achieve these goals. Here, we review evidence that targeting HDACs with low-molecular-weight inhibitors significantly decreases neuronal injury and improves functional outcome in multiple preclinical models of focal ischemia. These salutary effects emanate, in part, from modifications of chromatin and nonchromatin proteins that enhance adaptive gene expression or adaptive protein function. Together, the findings suggest that HDAC inhibition is a strategy capable of targeting diverse pathophysiologies of stroke with a wide therapeutic window.

Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator

2006 ◽  
Vol 95 (01) ◽  
pp. 166-173 ◽  
Author(s):  
Li Zhang ◽  
Zheng Zhang ◽  
Xianshuang Liu ◽  
Ann Hozeska ◽  
Nancy Stagliano ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Vascular Function ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Therapeutic Window ◽  
Vascular Events ◽  
Tissue Plasminogen

SummaryStroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib,a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis,inflammatory responses,and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-κB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-κB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.

scholarly journals HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies

2018 ◽  
Vol 215 (12) ◽  
pp. 3194-3212 ◽  
Author(s):  
Isabelle J. Marié ◽  
Hao-Ming Chang ◽  
David E. Levy
Keyword(s):  
Autoimmune Diseases ◽  
Histone Deacetylases ◽  
Elongation Factor ◽  
Positive Function ◽  
Transcriptional Elongation ◽  
Hdac Inhibition ◽  
Transcriptional Initiation ◽  
Inducible Promoters ◽  
The Common

In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN-stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetyltransferase and deacetylase activities that maintains a steady-state pool of free Brd4 available for recruitment to inducible promoters. An ISG expression signature is a hallmark of interferonopathies and other autoimmune diseases. Combined inhibition of HDAC1/2 and Brd4 resolved the aberrant ISG expression detected in cells derived from patients with two inherited interferonopathies, ISG15 and USP18 deficiencies, defining a novel therapeutic approach to ISG-associated autoimmune diseases.

scholarly journals The Two Pathophysiologies of Focal Brain Ischemia: Implications for Translational Stroke Research

2012 ◽  
Vol 32 (7) ◽  
pp. 1310-1316 ◽  
Author(s):  
Konstantin-Alexander Hossmann
Keyword(s):  
Vascular Occlusion ◽  
Maximum Size ◽  
Focal Ischemia ◽  
Therapeutic Window ◽  
Stroke Research ◽  
Naturally Occurring ◽  
Free Interval ◽  
Postischemic Recirculation ◽  
Primary Core ◽  
Focal Brain Ischemia

Brain injury after focal ischemia evolves along two basically different pathophysiologies, depending on the severity of the primary flow reduction and the dynamics of postischemic recirculation. In permanent and gradually reversed focal ischemia as after thromboembolic occlusion, primary core injury is irreversible but the expansion of the core into the penumbra can be alleviated by hemodynamic and molecular interventions. Such alleviation can only be achieved within 3 hours after the onset of ischemia because untreated core injury expands to near maximum size during this interval. In promptly reversed transient ischemia as after mechanical vascular occlusion, primary core injury may recover but a secondary delayed injury evolves after a free interval of as long as 6 to 12 hours. This injury can be alleviated throughout the free interval but the longer window is without clinical relevance because transient mechanical vascular occlusion is not a model of naturally occurring stroke. As this difference is widely ignored in stroke research, most clinical trials have been designed with a far too long therapeutic window, which explains their failure. Transient mechanical vascular occlusion models should, therefore, be eliminated from the repertoire of preclinical stroke research.

scholarly journals Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate versus Heparin

2017 ◽  
Vol 26 (1) ◽  
pp. 71-81 ◽  
Author(s):  
Elisabet Gustafson ◽  
Sana Asif ◽  
Huda Kozarcanin ◽  
Graciela Elgue ◽  
Staffan Meurling ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Dextran Sulfate ◽  
Cell Loss ◽  
Hepatocyte Transplantation ◽  
Low Molecular Weight ◽  
Cascade Systems ◽  
Cell Counts ◽  
Compatible Blood

Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 μg/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze–thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze–thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 μg/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation.

scholarly journals Dose Effect Evaluation and Therapeutic Window of the Neuro-EPO Nasal Application for the Treatment of the Focal Ischemia Model in the Mongolian Gerbil

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Iliana Sosa Teste ◽  
Yuneidys Mengana Tamos ◽  
Yamila Rodríguez Cruz ◽  
Adriana Muñoz Cernada ◽  
Janette Cruz Rodríguez ◽  
...  
Keyword(s):  
Brain Ischemia ◽  
Mongolian Gerbil ◽  
Neuroprotective Effect ◽  
Developed Countries ◽  
Focal Ischemia ◽  
Exploratory Activity ◽  
Dose Effect ◽  
Therapeutic Window ◽  
Average Dose ◽  
Thalamic Nuclei

Cerebrovascular disease is the third leading cause of death and the leading cause of disability in Cuba and in several developed countries. A possible neuroprotective agent is the rHu-EPO, whose effects have been demonstrated in models of brain ischemia. The Neuro-EPO is a derivative of the rHu-EPO that avoids the stimulation of erythropoiesis. The aim of this study was to determine the Neuro-EPO delivery into the central nervous system (CNS) to exert a neuroprotective effect in cerebral ischemia model of the Mongolian gerbil. The Neuro-EPO in a rate of 249.4 UI every 8 hours for 4 days showed 25% higher viability efficacy (), improving neurological score and behavior of the spontaneous exploratory activity, the preservation of CA3 areas of the hippocampus, the cortex, and thalamic nuclei in the focal ischemia model of the Mongolian gerbil. In summary, this study, the average dose-used Neuro-EPO (249.4 UI/10 μL/every 8 hours for 4 days), proved to be valid indicators of viability, neurological status, and spontaneous exploratory activity, being significantly lower than that reported for the systemically use of the rHu-EPO as a neuroprotectant. Indeed, up to 12 h after brain ischemia is very positive Neuro-EPO administration by the nasal route as a candidate for neuroprotection.

scholarly journals Histone Deacetylase Inhibitor Impairs Plasminogen Activator Inhibitor-1 Expression via Inhibiting TNF-α-Activated MAPK/AP-1 Signaling Cascade

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Wei-Lin Chen ◽  
Joen-Rong Sheu ◽  
Che-Jen Hsiao ◽  
Shih-Hsin Hsiao ◽  
Chi-Li Chung ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Histone Deacetylases ◽  
Plasminogen Activator Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Hdac Inhibition ◽  
Plasminogen Activator Inhibitor 1 ◽  
Hdac Activity ◽  
Mitogen Activated Protein ◽  
Activator Inhibitor ◽  
Pai 1

Tumor necrosis factor-(TNF-)-αupregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF-αor HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF-α-induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF-αin the presence or absence of them-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF-α-induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF-α-activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases.

Antipsychotic efficacy: Relationship to optimal D2-receptor occupancy

2007 ◽  
Vol 22 (5) ◽  
pp. 267-275 ◽  
Author(s):  
Luca Pani ◽  
Luigi Pira ◽  
Giorgio Marchese
Keyword(s):  
Atypical Antipsychotics ◽  
D2 Receptor ◽  
Receptor Occupancy ◽  
Antipsychotic Agents ◽  
Therapeutic Window ◽  
Therapeutic Effects ◽  
Preclinical Models ◽  
Biochemical Interaction ◽  
The Relationship ◽  
The Brain

AbstractClinically important differences exist between antipsychotic agents and formulations in terms of safety and tolerability. Features of the biochemical interaction between the antipsychotic and the D2-receptor may underlie these differences. This article reviews current information on the relationship between antipsychotic receptor occupancy and clinical response. A literature search was performed using the keywords ‘antipsychotic or neuroleptic’, ‘receptor’ and ‘occupancy’ and ‘dopamine’ and ‘D2’ supplemented by the authors’ knowledge of the literature. Imaging and clinical data have generally supported the hypotheses that optimal D2-receptor occupancy in the striatum lies in a ‘therapeutic window’ between ∼65 and ∼80%, however, pharmacokinetic and pharmacodynamic properties of a drug should also be taken into account to fully evaluate its therapeutic effects. Additional research, perhaps in preclinical models, is needed to establish D2-receptor occupancy in various regions of the brain and the optimal duration of D2-receptor blockade in order to maximise efficacy and tolerability profiles of atypical antipsychotics and thereby improve treatment outcomes for patients with schizophrenia.

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