scholarly journals Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Zachariah Bertels ◽  
Harinder Singh ◽  
Isaac Dripps ◽  
Kendra Siegersma ◽  
Alycia F Tipton ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Neuronal Plasticity ◽  
Neurite Growth ◽  
Migraine Treatment ◽  
Histone Deacetylase 6 ◽  
Calcitonin Gene ◽  
Prevalent Disease ◽  
Hdac6 Inhibitor ◽  
Physiological Correlate ◽  
Primary Substrate

Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

scholarly journals Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

2020 ◽  
Author(s):  
Zachariah Bertels ◽  
Harinder Grewal ◽  
Isaac Dripps ◽  
Kendra Siegersma ◽  
Alycia Laboy ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Neuronal Plasticity ◽  
Neurite Growth ◽  
Migraine Treatment ◽  
Histone Deacetylase 6 ◽  
Calcitonin Gene ◽  
Prevalent Disease ◽  
Hdac6 Inhibitor ◽  
Physiological Correlate ◽  
Primary Substrate

Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

scholarly journals Enxaqueca Crónica e Refratária: Como Diagnosticar e Tratar

2020 ◽  
Vol 33 (11) ◽  
pp. 753
Author(s):  
Elsa Parreira ◽  
Isabel Luzeiro ◽  
José Maria Pereira Monteiro
Keyword(s):  
Chronic Migraine ◽  
Medication Overuse Headache ◽  
Botulinum Toxin Type A ◽  
Botulinum Toxin Type ◽  
Migraine Treatment ◽  
The Novel ◽  
Personal Impact ◽  
Calcitonin Gene ◽  
Migraine Pathogenesis ◽  
Refractory Migraine

Migraine is highly prevalent and carries a significant personal, social and economic burden. It is the second cause of disability (years living with disability) worldwide and the first cause under 50 years of age. Chronic migraine (occurring for more than 15 days a month) and refractory migraine (treatment resistant), especially when there is also analgesic overuse, are the most disabling forms of migraine. These three disorders (chronic migraine, refractory migraine and medication overuse headache) are particularly difficult to treat. This article reviews their epidemiology, clinical presentation, diagnostic criteria, risk factors, comorbidities and social and personal impact. The therapeutic options available are discussed and focused on a multidisciplinary approach, non-pharmacological interventions treatment of comorbidities and avoiding analgesic overuse. Prophylactic treatments are mandatory and include the oral prophylactic treatments (topiramate), botulinum toxin type A and the novel monoclonal antibodies against calcitonin gene related peptide or its receptor, which are the first migraine preventive medicines developed specifically to target migraine pathogenesis. In refractory cases, multiple therapies are required including neurostimulation.

scholarly journals A novel orally active HDAC6 inhibitor T-518 shows a therapeutic potential for Alzheimer’s disease and tauopathy in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomohiro Onishi ◽  
Ryouta Maeda ◽  
Michiko Terada ◽  
Sho Sato ◽  
Takahiro Fujii ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Drug Candidate ◽  
Histone Deacetylase 6 ◽  
Cellular Assays ◽  
Age Related ◽  
Acetylation State ◽  
Hdac6 Inhibitor ◽  
Orally Active

AbstractAccumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Those diseases are collectively termed tauopathies. Tau pathology is associated with axonal degeneration because tau binds to microtubules (MTs), a component of axon and regulates their stability. The acetylation state of MTs contributes to stability and histone deacetylase 6 (HDAC6) is a major regulator of MT acetylation status, suggesting that pharmacological HDAC6 inhibition could improve axonal function and may slow the progression of tauopathy. Here we characterize N-[(1R,2R)-2-{3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}cyclohexyl]-2,2,3,3,3-pentafluoropropanamide (T-518), a novel, potent, highly selective HDAC6 inhibitor with clinically favorable pharmacodynamics. T-518 shows potent inhibitory activity against HDAC6 and superior selectivity over other HDACs compared with the known HDAC6 inhibitors in the enzyme and cellular assays. T-518 showed brain penetration in an oral dose and blocked HDAC6-dependent tubulin deacetylation at Lys40 in mouse hippocampus. A 2-week treatment restored impaired axonal transport and novel object recognition in the P301S tau Tg mouse, tauopathy model, while a 3-month treatment also decreased RIPA-insoluble tau accumulation. Pharmaceutical inhibition of HDAC6 is a potential therapeutic strategy for tauopathy, and T-518 is a particularly promising drug candidate.

scholarly journals HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma

2021 ◽  
Vol 22 (3) ◽  
pp. 1341
Author(s):  
Sang Wu Lee ◽  
Soo-Keun Yeon ◽  
Go Woon Kim ◽  
Dong Hoon Lee ◽  
Yu Hyun Jeon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Factor Kappa B ◽  
Selective Inhibitor ◽  
Signal Transducer ◽  
Histone Deacetylase 6 ◽  
Cell Growth Inhibition ◽  
Cancer Cell Growth ◽  
Extracellular Signal ◽  
Hdac6 Inhibitor ◽  
Transcription 3

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.

scholarly journals Effect of Calcitonin Gene-Related Peptide Receptor Antagonists on Migraine Treatment: A Meta-Analysis

2021 ◽  
Author(s):  
Jiyoung Kim ◽  
Kyoungjune Pak ◽  
Gha-Hyun Lee ◽  
Jae Wook Cho ◽  
Hyun-Woo kim
Keyword(s):  
Meta Analysis ◽  
Calcitonin Gene Related Peptide ◽  
Migraine Treatment ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Acute Migraine Treatment

Abstract Background: The pathophysiology of migraine has been researched incessantly, and it has been suggested that calcitonin gene-related peptide (CGRP) is associated with migraine attacks. CGRP receptor blockers are attracting attention for migraine prevention and treatment of acute episodes, and CGRP receptor antagonists have been shown to be effective in treating acute migraine headaches. This meta-analysis aimed to assess the effect of available CGRP receptor antagonists, focusing on their therapeutic doses for acute migraine treatment.Methods: We performed a systematic search of MEDLINE (from inception to March 2021) and EMBASE (from inception to March 2021) for English publications using the keywords “migraine” and “Calcitonin gene-related peptide,” limited to human studies.Results: Five studies that focused on examining the effects of CGRP receptor antagonists on acute migraine treatment met the eligibility criteria for this meta-analysis. The pooled analysis demonstrated that the CGRP receptor antagonist improved freedom from pain (OR=2.066, 95% confidence interval [CI] 1.766–2.418, I2=0%), absence of bothersome symptoms (OR=1.606, 95% CI=1.408–1.830, I2=0%), pain relief (OR=1.791, 95% CI=1.598–2.008, I2=0%), and freedom from nausea (OR=1.361, 95% CI=1.196–1.548, I2=0%), significantly more than the placebo. Conclusions: CGRP receptor antagonists are effective for acute migraine treatment and are expected to be used clinically as emerging therapeutic agents.

Abstract 502: Inhibition of Histone Deacetylase 6 Protects Human Induced Pluripotent Stem Cells-derived Cardiomyocytes Through Inhibition of Autophagy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Narasimman Gurusamy ◽  
SHEEJA RAJASINGH ◽  
Vinoth Sigamani ◽  
Shivaani Kirankumar ◽  
Jayavardini Vasanthan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Induced Pluripotent Stem Cells ◽  
Histone Deacetylase ◽  
Pluripotent Stem Cells ◽  
Histone Deacetylase 6 ◽  
Hdac6 Inhibitor ◽  
Induced Pluripotent ◽  
First Time

Introduction: Autophagy is known to play an important role in mediating cardiac hypertrophy. However, the mechanism is poorly understood. Since the protein histone deacetylase 6 (HDAC6) contributes to cardiac dysfunction in response to angiotensin II (AngII) signaling, we have examined the role of HDAC6 inhibitor tubastatin A (TBA) in AngII-induced remodeling in human induced pluripotent stem cells-derived cardiomyocytes (iCMCs). Hypothesis: We hypothesize that the inhibition of HDAC6 protects iCMCs from AngII-induced cardiac hypertrophy through inhibition of autophagy. Methods and Results: We have generated and characterized induced pluripotent stem cells from human adult skin fibroblasts and subsequently differentiated them into iCMCs. Treatment with 10 μM angiotensin II for 24 hrs increased the HDAC6 activity and lead to hypertrophy in iCMCs. The AngII-induced hypertrophy, and the excessive contractility in iCMCs were reversed by the inhibition of HDAC6 with TBA (1 μM for 24 hours). The number of LC3-positive iCMCs, and the mRNA and the protein expression of autophagic genes Beclin-1, LC3, and p62 were increased by the presence of AngII, and the anti-autophagic gene Bcl2 was decreased by AngII. The inhibition of HDAC6 with TBA reversed the AngII-mediated changes in the autophagic genes expressions in iCMCs. Autophagic vacuoles were identified with monodansylcadaverine (MDC, green) and lysosomes with LysoTracker (red) (Fig. 1A) . The number of autophagolysosomes were increased by AngII, and this was decreased with TBA in iCMCs (Fig. 1B) . Conclusions: Our report indicates for the first time that the AngII-induced cardiac hypertrophy-mediated autophagy is effectively inhibited by the suppression of HDAC6 in human iCMCs.

Early onset of effect of onabotulinumtoxinA for chronic migraine treatment: Analysis of PREEMPT data

Cephalalgia ◽  
2019 ◽  
Vol 39 (8) ◽  
pp. 945-956 ◽  
Author(s):  
David W Dodick ◽  
Stephen D Silberstein ◽  
Richard B Lipton ◽  
Ronald E DeGryse ◽  
Aubrey Manack Adams ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Migraine Treatment ◽  
Phase 3 ◽  
Double Blind ◽  
Registration Number ◽  
Treatment Analysis ◽  
Prophylaxis Therapy ◽  
Probable Migraine ◽  
Multiple Treatments ◽  
Post Hoc

Background The Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials demonstrated efficacy/tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis assessed time of onset of onabotulinumtoxinA after the first treatment in total and responder populations and consistency weekly through five treatment cycles. Methods In the 24-week, double-blind, placebo-controlled phase of PREEMPT, individuals were randomized 1:1 to onabotulinumtoxinA (155-195 U) or placebo every 12 weeks for two cycles. The primary pooled efficacy variable was change in headache days per 28 days at week 24. We assessed change in headache and migraine/probable migraine (hereafter migraine) days/week compared with baseline week 4. Results Baseline mean (SD) headache days/week (week 4 of baseline) for onabotulinumtoxinA (n = 688) and placebo (n = 696) were similar (4.8 [1.6] vs. 4.8 [1.6] days/week, respectively), as were migraine days/week (4.6 [1.7] vs. 4.6 [1.7] days/week). The effect of onabotulinumtoxinA on change in headache and migraine days/week was significantly greater than placebo at week 1, persisting from week 3 after the first treatment (−1.6 [2.2] vs. −1.1 [2.2] headache days/week [  p < 0.001] and −1.6 [2.2] vs. −1.1 [2.2] migraine days/week [  p < 0.001]). Headache and migraine days decreased in onabotulinumtoxinA responders beginning 1 week after treatment 1. Conclusions Treatment with onabotulinumtoxinA is associated with significant reductions in headache and migraine days/week at week 1, persisting after week 3, compared with placebo. Combined with earlier reports showing onabotulinumtoxinA treatment results in a persistent and progressive reduction in headache days over 56 weeks, it is suggested peak benefit may require multiple treatments. Trial registration number ClinicalTrials.gov: NCT00156910 and NCT00168428.

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