title: Effect of histone deacetylase inhibitor JNJ-26481585 in pain.
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.
authors.affiliation: Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Capasso
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Manners
authors.forename: Rehman A
authors.initials: RA
authors.lastname: Quershi
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Tian
authors.forename: Ruby
authors.initials: R
authors.lastname: Gao
authors.forename: Huijuan
authors.initials: H
authors.lastname: Hu
authors.forename: James E
authors.initials: JE
authors.lastname: Barrett
authors.forename: Ahmet
authors.initials: A
authors.lastname: Sacan
authors.forename: Seena K
authors.initials: SK
authors.lastname: Ajit
mesh_terms: D000588:Amines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D000077206:Gabapentin; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects*; D006877:Hydroxamic Acids / Q000009:adverse effects*; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009437:Neuralgia / Q000209:etiology* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D016328:NF-kappa B; C541788:quisinostat; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin
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