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Effect of histone deacetylase inhibitor JNJ-26481585 in pain
Journal article   Peer reviewed

Effect of histone deacetylase inhibitor JNJ-26481585 in pain

Kathryn E Capasso, Melissa T Manners, Rehman A Quershi, Yuzhen Tian, Ruby Gao, Huijuan Hu, James E Barrett, Ahmet Sacan and Seena K Ajit
Journal of molecular neuroscience, v 55(3), pp 570-578
Mar 2015
DOI: https://doi.org/10.1007/s12031-014-0391-7
PMID: 25085711
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Spinal Cord - drug effects Spinal Cord - metabolism Calcium Channels - metabolism Hyperalgesia - metabolism Hydroxamic Acids - adverse effects Mice, Inbred C57BL Neuralgia - metabolism gamma-Aminobutyric Acid - pharmacology Male NF-kappa B - metabolism Interleukin-1beta - genetics Macrophages - metabolism Animals Antineoplastic Agents - adverse effects Cyclohexanecarboxylic Acids - pharmacology Interleukin-1beta - metabolism Neuralgia - etiology Hyperalgesia - etiology Macrophages - drug effects Mice Amines - pharmacology Calcium Channels - genetics Histone Deacetylase Inhibitors - adverse effects
Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585-treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose- and time-dependent activation of nuclear factor-kappaB and interleukin-1β increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin.

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20 citations in Web of Science
23 citations in Scopus

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UN Sustainable Development Goals (SDGs)

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#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Neurosciences
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