The Antagonism of the Prokineticin System Counteracts Bortezomib Induced Side Effects: Focus on Mood Alterations.

Giada Amodeo,Paola Sacerdote,Vincenzo Conte,Gianfranco Balboni,Patrizia Sartori,Patrizia Procacci,Silvia Franchi,Benedetta Verduci

doi:10.3390/ijms221910256

Giada Amodeo, Paola Sacerdote + Show 6 more

Open Access

https://doi.org/10.3390/ijms221910256

Copy DOI

Abstract

The development of neuropathy and of mood alterations is frequent after chemotherapy. These complications, independent from the antitumoral mechanism, are interconnected due to an overlapping in their processing pathways and a common neuroinflammatory condition. This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation. We also verify if the therapeutic treatment with the antagonist of the prokineticin (PK) system PC1, which is known to contrast pain and neuroinflammation, can prevent mood alterations. Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety (dark light and marble burying test), depression (sucrose preference and swimming test) and supraspinal neuroinflammation were checked at the end of the protocol. BTZ treated neuropathic mice develop anxiety and depression. The presence of mood alterations is related to the presence of neuroinflammation and PK system activation in prefrontal cortex, hippocampus and hypothalamus with high levels of PK2 and PKR2 receptor, IL-6 and TNF-α, TLR4 and an upregulation of glial markers. PC1 treatment, counteracting pain, prevented the development of supraspinal inflammation and depression-like behavior in BTZ mice.

Highlights

The number of cancer survivors is increasing; the development of side effects due to chemotherapeutic treatment is frequent
This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation
Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety, depression and supraspinal neuroinflammation were checked at the end of the protocol

Summary

Introduction

The number of cancer survivors is increasing; the development of side effects due to chemotherapeutic treatment is frequent. Chemotherapy-induced painful neuropathy (CIPN), chemotherapy-induced cognitive impairment (CICI) and psychological distress such as anxiety and depression deserve particular attention considering their incidence and impact on patient’s life quality [1–4]. All these complications are independent from the antitumoral effect and are common to newer chemotherapeutic agents such as proteasome inhibitors [5,6]. Current theories suggest that long-term pain triggers neural changes that would be responsible for affective and cognitive alterations such as anxiety and depression [11,12,14–17]. We identified PK2 as a key molecule in the neuroinflammatory pathway that moving from the peripheral (PNS) to central nervous system (CNS) is important for pain processing [28,29]. Intracerebroventricular injection of PK2 in mice leads to increase in anxietyand depressive-like behavior while mice deficient in pk gene display reduced anxiety and depression [30]

Objectives

Methods

Results

Conclusion