Targeting prokineticin system counteracts hypersensitivity, neuroinflammation, and tissue damage in a mouse model of bortezomib-induced peripheral neuropathy

Giorgia Moschetti,Valentina Onnis,Alberto Panerai,Roberta Lattanzi,Vincenzo Conte,Giada Amodeo,Daniela Maftei,Paola Sacerdote,Gianfranco Balboni,Patrizia Sartori,Silvia Franchi,Patrizia Procacci

doi:10.1186/s12974-019-1461-0

Abstract

BackgroundNeuropathy is a dose-limiting side effect of many chemotherapeutics, including bortezomib. The mechanisms underlying this condition are not fully elucidated even if a contribution of neuroinflammation was suggested. Here, we investigated the role of a chemokine family, the prokineticins (PKs), in the development of bortezomib-induced peripheral neuropathy (BIPN), and we used a PK receptor antagonist to counteract the development and progression of the pathology.MethodsNeuropathy was induced in male C57BL/6J mice by using a protocol capable to induce a detectable neuropathic phenotype limiting systemic side effects. The presence of allodynia (both mechanical and thermal) and thermal hyperalgesia was monitored over time. Mice were sacrificed at two different time points: 14 and 28 days after the first bortezomib (BTZ) injection. At these times, PK system activation (PK2 and PK-Rs), macrophage and glial activation markers, and cytokine production were evaluated in the main station involved in pain transmission (sciatic nerve, DRG, and spinal cord), and the effect of a PK receptors antagonist (PC1) on the same behavioral and biochemical parameters was assessed. Structural damage of DRG during BTZ treatment and an eventual protective effect of PC1 were also evaluated.ResultsBTZ induces in mice a dose-related allodynia and hyperalgesia and a progressive structural damage to the DRG. We observed a precocious increase of macrophage activation markers and unbalance of pro- and anti-inflammatory cytokines in sciatic nerve and DRG together with an upregulation of GFAP in the spinal cord. At higher BTZ cumulative dose PK2 and PK receptors are upregulated in the PNS and in the spinal cord. The therapeutic treatment with the PK-R antagonist PC1 counteracts the development of allodynia and hyperalgesia, ameliorates the structural damage in the PNS, decreases the levels of activated macrophage markers, and prevents full neuroimmune activation in the spinal cord.ConclusionsPK system may be a strategical pharmacological target to counteract BTZ-induced peripheral neuropathy. Blocking PK2 activity reduces progressive BTZ toxicity in the DRG, reducing neuroinflammation and structural damage to DRG, and it may prevent spinal cord sensitization.

Highlights

Neuropathy is a dose-limiting side effect of many chemotherapeutics, including bortezomib
The activation of PK system in the peripheral nerves, dorsal root ganglia (DRG), and spinal cord correlates with the presence of neuroinflammation and the development of experimental neuropathic pain induced in mice by damage to the sciatic nerve [14, 20, 21] or by a metabolic disorder like diabetes [13]
In order to do that, we evaluated in sciatic nerve, DRG, and spinal cord the activation of PK system and neuroinflammation during the pathology progression performing biochemical and ultrastructural analysis 14 days after the first BTZ treatment and at the end of the chemotherapeutic schedule

Summary

Introduction

Neuropathy is a dose-limiting side effect of many chemotherapeutics, including bortezomib. Penetration of chemotherapeutic agents into the central nervous system is relatively poor, whereas chemotherapeutics can cross the blood-nerve barrier, accumulating in the dorsal root ganglia (DRG) and peripheral nerve, exerting a toxic action and making these stations the main direct target of drug cytotoxicity This condition leads to immune cell, in particular macrophages, infiltration and activation in these areas, promoting neuropathy progression [8,9,10]. The activation of PK system in the peripheral nerves, DRG, and spinal cord correlates with the presence of neuroinflammation and the development of experimental neuropathic pain induced in mice by damage to the sciatic nerve [14, 20, 21] or by a metabolic disorder like diabetes [13] In these experimental models, the treatment with antagonists of PK system was able to contrast or prevent the neuropathic symptomatology. On the basis of these considerations, our hypothesis is that PK system could represent a strategical target to counteract BIPN

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