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Effect of Histone Deacetylase Inhibitor JNJ-26481585 in Pain

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Abstract

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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Acknowledgments

This study was supported by funds from Drexel University College of Medicine and Rita Allen Foundation grant to Seena Ajit. We thank members of the Kimmel Cancer Center Cancer for microarray processing.

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Authors and Affiliations

  1. Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA

    Kathryn E. Capasso, Melissa T. Manners, Yuzhen Tian, Ruby Gao, Huijuan Hu, James E. Barrett & Seena K. Ajit

  2. School of Biomedical Engineering, Science & Health Systems, Drexel University, 245 North 15th Street, Mail Stop 488, Philadelphia, PA, 19104, USA

    Rehman A. Quershi & Ahmet Sacan

  3. Albany Medical College, Albany, NY, 12208, USA

    Kathryn E. Capasso

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  1. Kathryn E. Capasso
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  2. Melissa T. Manners
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  9. Seena K. Ajit
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Correspondence to Seena K. Ajit.

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Kathryn E. Capasso and Melissa T. Manners contributed equally to this work.

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Capasso, K.E., Manners, M.T., Quershi, R.A. et al. Effect of Histone Deacetylase Inhibitor JNJ-26481585 in Pain. J Mol Neurosci 55, 570–578 (2015). https://doi.org/10.1007/s12031-014-0391-7

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