Abstract
Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.
Highlights
Several mechanisms are involved in Chemotherapy-induced neuropathy (CIN), and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation
Spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, prokineticin 2 (PK2), and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1
Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many cancer therapeutic agents, including bortezomib (BTZ), a first-generation proteasome inhibitor widely used for the treatment of multiple myeloma [1,2,3]
Summary
Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many cancer therapeutic agents, including bortezomib (BTZ), a first-generation proteasome inhibitor widely used for the treatment of multiple myeloma [1,2,3]. The present study aimed to evaluate possible relationships among epigenetic mechanisms and prokineticin system involvement in the development and maintenance of bortezomib-induced neuropathy To this end, alterations in the spinal cord levels of KDM6A and PPARα/ PPARγ, as well as those of PK2 and pro-inflamma3toorfy cytokines IL-6 and IL-1β, were assessed in the presence or absence of a specific PKR antagonist, in a model of BTZ-induced neuropathic pain. The inhibitory role of PK2 on PPARs that, when activated, dampens inflammatory responses and relief pain, further sustains a relevant role of PK2 as pro-inflammatory mediator, since it stimulates proinflammatory and pronociceptive factors and blunts the endogenous anti-inflammatory responses [13] These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated to BTZ painful neuropathy, and underline a role of the PK system in sustaining the increase of specific proinflammatory cytokines through the regulation of the histone demethylase enzyme KDM6A gene expression
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