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Role of Histone Deacetylase Inhibitor in Diabetic Painful Neuropathy

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Abstract

Diabetic painful neuropathy (DPN) is one of the most detrimental complications of diabetes. Alterations in neuroinflammatory mediators play significant roles in the development of DPN. Infiltration of the neutrophils and monocyte/macrophages contributes substantial role in the degenerative process of the distal sciatic nerve by forming neutrophil extracellular traps (NETs) under diabetic condition. Citrullination of histones due to increase in protein arginine deiminase (PAD) enzyme activity under hyperglycemia may promote NET formation, which can further increase the cytokine production by activating macrophages and proliferation of neutrophils. This study reveals that the increase in histone deacetylases (HDAC) is crucial in DPN and inhibition of HDAC using HDAC inhibitor (HDACi) FK228 would suppress NETosis and alleviate diabetic nerve degeneration and pain. FK228, also known as romidepsin, is FDA approved for the treatment of cutaneous T-cell lymphoma yet the molecular mechanisms of this drug are not completely understood in DPN. In this study, type 2 diabetic (T2D) mice with pain were treated with HDACi, FK228 1 mg/kg; I.P. 2 × /week for 3 weeks. The results demonstrate that FK228 treatment can alleviate thermal hyperalgesia and mechanical allodynia significantly along with changes in the expression of HDACs in the dorsal root ganglia (DRG) and spinal cord dorsal horn neurons of diabetic animals. The results also indicate that FK228 treatment can alter the expression of neutrophil elastase (NE), extracellular or cell free DNA (cfDNA), citrullinated histone-3 (CitH3), PADI4, growth-associated protein (GAP)-43, and glucose transporter (GLUT)-4. Overall, this study suggests that FK228 could amend the expression of nerve regeneration markers and inflammatory mediators in diabetic animals and may offer an alternative treatment approach for DPN.

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Data Availability

All data generated or analyzed during the current study are included in this published article. Additional data will be available from the corresponding author on reasonable request.

Abbreviations

DRG:

Dorsal root ganglia

HDAC:

Histone deacetylase

T2D:

Type 2 diabetes

TLR4:

Toll-like receptor 4

H3K9ac:

Histone 3 lysine (K) 9 acetylation

FK228:

Romidepsin

NE:

Neutrophil elastase

cfDNA:

Cell-free DNA

CitH3:

Citrullinated histone 3

GAP43:

Growth-associated protein 43

PAD:

Peptidyl arginine deiminase

NET:

Neutrophil extracellular trap

GLUT4:

Glucose transporter type 4

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Acknowledgements

We thank our Laboratory Animal Resources Center (LARC) staffs for taking care of the animals.

Funding

This work was supported by the start-up fund for Munmun Chattopadhyay from Texas Tech University Health Sciences Center, El Paso, TX.

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Authors and Affiliations

  1. Department of Molecular and Translational Medicine, Center of Emphasis in Diabetes and Metabolism, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA

    Vikram Thakur & Munmun Chattopadhyay

  2. Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA

    Mayra A. Gonzalez & Munmun Chattopadhyay

  3. Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA

    Maria Parada, Robert D. Martinez & Munmun Chattopadhyay

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  1. Vikram Thakur
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  5. Munmun Chattopadhyay
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Contributions

Vikram Thakur (VT) and Munmun Chattopadhyay (MC) designed the study. VT, Mayra Gonzalez conducted the animal experiments and collected data. Maria Parada and Robert Martinez performed tissue analysis and in vitro studies. All authors were involved in analysis and interpretation of the data, drafting and finalizing the manuscript. MC supervised the study and wrote the manuscript.

Corresponding author

Correspondence to Munmun Chattopadhyay.

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Ethics Approval

All animal experiments were performed in compliance with approved institutional animal care and use protocols (IACUC, TTUHSC El Paso, TX) in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) approved facility. All animal experiments followed the instructions from “Guide for the Care and Use of Laboratory Animals” 8th edition, 2011.

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Supplementary Information

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Supplementary file1. Increased expression of HDAC2 in hyperglycemic DRG neuronal cells ameliorated by FK228 treatment

High glucose exposure (25mM) for 48 hours increased the expression of HDAC2 significantly in F11 DRG cell line when compared with normoglycemic condition. Overnight treatment with FK228 lowered the HDAC2 expression in hyperglycemic cells that were exposed to high glucose 24 hours prior to treatment. (EPS 5306 KB)

12035_2023_3701_MOESM2_ESM.eps

Supplementary file2. Increased H3K9 acetylation was observed in hyperglycemic DRG neuronal cell line treated with HDAC inhibitor

Immunocytochemical studies revealed that treatment with HDAC inhibitor FK228 increased H3K9 acetylation in treated hyperglycemic DRG neurons compared to hyperglycemic and normoglycemic DRG neuronal cell line. Although not significant, hyperglycemic DRG cells showed a downregulation of H3K9 acetylation compared to normoglycemic DRG neuronal cells. (EPS 12639 KB)

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Thakur, V., Gonzalez, M.A., Parada, M. et al. Role of Histone Deacetylase Inhibitor in Diabetic Painful Neuropathy. Mol Neurobiol 61, 2283–2296 (2024). https://doi.org/10.1007/s12035-023-03701-4

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