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Charcot‐Marie‐Tooth disease type 2D (CMT2D), is a hereditary peripheral neuropathy caused by mutations in the gene encoding glycyl‐tRNA synthetase (GARS1). Here, human induced pluripotent stem cell (hiPSC)‐based models of CMT2D bearing mutations in GARS1 and their use for the identification of predictive biomarkers amenable to therapeutic efficacy screening is described. Cultures containing spinal cord motor neurons generated from this line exhibit network activity marked by significant deficiencies in spontaneous action potential firing and burst fire behavior. This result matches clinical data collected from a patient bearing a GARS1P724H mutation and is coupled with significant decreases in acetylated α‐tubulin levels and mitochondrial movement within axons. Treatment with histone deacetylase 6 inhibitors, tubastatin A and CKD504, improves mitochondrial movement and α‐tubulin acetylation in these cells. Furthermore, CKD504 treatment enhances population‐level electrophysiological activity, highlighting its potential as an effective treatment for CMT2D. [ABSTRACT FROM AUTHOR]

Background and Purpose: Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. CMT type 1A (CMT1A) accounts for approximately 50% of CMT patients and is linked to PMP22 gene duplication. Histone deacetylase-6 (HDAC6) has pleiotropic effects, such as regulating lipid homeostasis and cellular stress. Although HDAC6 has been regarded as a promising drug target for neurodegenerative diseases, its inhibition has not yet been tested in CMT1A. Here we have tested the therapeutic potential of CKD-504, a clinical stage HDAC6 inhibitor, in a mouse model of CMT1A EXPERIMENTAL APPROACH: The potency and selectivity of CKD-504 was evaluated, using a HDAC enzyme panel assay and western blots. The therapeutic potential of CKD-504 was evaluated using behavioural testing and electrophysiological assessments in the C22 mouse model of CMT1A. PMP22 protein expression and aggregation were analysed in mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves from C22 mice.Key Results: The HDAC6 inhibitor, CKD-504, modulated molecular chaperon proteins such as HSP90 and HSP70, which are involved in the folding/refolding of proteins such as PMP22. CKD-504 treatment restored myelination in both mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves of C22 mice and improved the axonal integrity of the sciatic nerve, leading to behavioural, electrophysiological, and histological improvements in C22 mice.Conclusion and Implications: A novel HDAC6 inhibitor, CKD-504, has potent therapeutic efficacy for CMT1A. [ABSTRACT FROM AUTHOR]

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The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Background: Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA)., Methods: CIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days. Arthritis score was assessed and histological analysis was performed by hematoxylin and eosin (H&E) stain. Cytotoxic T-lymphocyte associated protein (CTLA)-4 expression in induced Treg cells was analyzed and suppression assay was analyzed using Treg cells and effector T (Teff) cells isolated from naive C57BL/6 mice by flow cytometry. Cytokines were analyzed in peripheral blood mononuclear cells (PBMC) of five patients with RA by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Tumor necrosis factor (TNF) was analyzed using PMA- activated THP-1 cells by ELISA. Suppression assay was analyzed using Treg cells and Teff cells isolated from RA patients by flow cytometry., Results: In the CIA model, CKD-L and Tubastatin A significantly decreased the arthritis score. CKD-L increased CTLA-4 expression in Foxp3 + T cells and inhibited the proliferation of Teff cells in the suppression assay. In RA PBMC, CKD-L significantly inhibited TNF and interleukin (IL)-1β, and increased IL-10. CKD-L and Tubastatin A inhibited TNF secretion from PMA-activated THP-1 cells. CKD-L and ITF 2357 inhibited the proliferation of Teff cells in RA patients in the suppression assay. Tubastatin A had no effect on inhibition of proliferation., Conclusion: CKD-L decreased the arthritis score in CIA, reduced the expression of TNF and IL-1β, and increased the expression of IL-10 in PBMC from RA patients. CKD-L increased CTLA-4 expression and the suppressive function of Treg cells. These results suggest that CKD-L may have a beneficial effect in the treatment of RA.

The flower buds of Buddleja officinalis MAXIM (Loganiaceae) are used to treat headache and inflammatory diseases in traditional Korean medicine. In the present study, the neuroprotective effects of the methanolic extract of B. officinalis (BOME) and of its hexane fraction (BOHF) were investigated in a middle cerebral artery occlusion (MCAo, 120 min occlusion, 24 h reperfusion) Sprague-Dawley rat model. BOME or BOHF (100 mg/kg, p.o.) was twice administered 30 min before the onset of MCAo and 2 h after reperfusion. BOME and BOHF treated groups showed infarct volumes reduced by 33.9% and 68.2%, respectively, at 2 h occlusion. In BOHF treated animals, cyclooxygenase-2 and iNOS inductions were inhibited in ischemic hemispheres at both the mRNA and protein levels. Furthermore, in vitro studies showed that BOME and BOHF both inhibited LPS-induced nitric oxide production in BV-2 mouse microglial cells. These results suggest that the anti-inflammatory and the microglial activation inhibitory effects of B. officinalis extract may contribute to its neuroprotective effects in brain ischemia.