Human Intravenous Immunoglobulin Alleviates Neuropathic Symptoms in a Rat Model of Paclitaxel-Induced Peripheral Neurotoxicity.

Cristina Meregalli,Guido Cavaletti,Giulia Fumagalli,Carla Scali,Annalisa Canta,Laura Monza,Chiara Guarnieri,Paola Alberti,Elisa Ballarini,Eleonora Pozzi,Virginia Rodriguez-Menendez,Alessia Chiorazzi,Paola Marmiroli,Norberto Oggioni

doi:10.3390/ijms22031058

Abstract

The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors’ quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation.

Highlights

peripheral neurotoxicity (PIPN) is characterized by a distal-to-proximal nerve degeneration pattern and by the so called “PTX associated acute pain syndrome (PAPS)”, which has been suggested to be closely linked to the development of chronic PIPN [3] and is considered to be a specific type of neuropathic pain typical of PIPN [4]
PTX and PTX-intravenous immunoglobulin (IVIg) co-treatment were well tolerated by the animals during the experiment, it did not induce any significant difference in body weight compared to vehicletreated rats and no animals died during the study nor showed signs of distress
Since no data about their effects in PIPN are available, the results presented in this study fill this gap by reporting that preventive IVIg co-administration could be effective in alleviating PIPN nocifensive behavior and reducing intra-epidermal nerve fiber (IENF) loss after chemotherapy treatment withdrawal

Summary

Introduction

Paclitaxel (PTX) is a very effective anti-tubulin drug belonging to the family of taxanes. It is largely employed in the treatment of many solid tumors including breast, prostate, non-small cell lung, pancreatic and gynecological cancers [1]. Its use is often limited by the onset of PTX-induced peripheral neurotoxicity (PIPN), a common and potentially severe side-effect occurring in up to 87% of patients undergoing PTX chemotherapy regimen [2]. To better understand the mechanisms underlying PIPN, several animal models have been developed over the years [5,6,7], reaching a high level of reproducibility and similarity with the clinical pictures observed in patients undergoing PTX-based chemotherapy

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