DIFFERENT DEGREES OF MACROPHAGE INFILTRATION IN PRECLINICAL MODELS OF ANTITUBULIN AGENTS-INDUCED PERIPHERAL NEUROTOXICITY

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most important side-effect of several anticancer drugs, including Paclitaxel (PTX, taxane family) and Vincristine (VCR, vinca alkaloid family). The mechanisms involved in CIPN onset are not completely understood; several neurotoxic hypotheses have been proposed, among which the role of the neuroinflammation process is emerging. In particular, different studies demonstrated that the role of macrophage infiltration correlated to neurotoxicity and sensory nervous system sensitization. We investigated the presence of macrophage infiltratE in two well-assessed preclinical models of PTX- and VCR- induced peripheral neurotoxicity. Female Wistar rats were divided in control (CTRL), PTX- (10mg/kg i.v. q7dx4 ws) and VCR- (0.2mg/kg i.v. q7dx4 ws) treated groups. The development of CIPN was confirmed by neurophysiological, morphological examinations and behavioral tests, whereas macrophage infiltration and description were obtained by immunoistochemical analyses. PTX and VCR chronic administration induced different degrees of axonal damage and macrophage infiltration in peripheral nerves. In particular, macrophage infiltrate was detected from the first week of treatment in PTX-treated animals, with a progressive increase until the end of treatment. On the contrary, VCR treatment induced a milder macrophage infiltration detected after 2 weeks of treatment, which remained constant until the end of the experiment. Moreover, immunoistochemical analyses evidenced that all the infiltrating cells had a pro-inflammatory phenotype. CIPN was detected from the second week after both anticancer administrations, with a stronger severity in PTX group compared to VCR one. These preliminary results evidence a different amount of macrophage infiltration in CIPN induced by PTX and VCR. Since the detection of inflammatory infiltrate was early and sustained until the end of the drug treatment, it could have a relevant role into the onset and progression of CIPN or painful symptoms. Moreover, the different pattern of macrophage infiltration suggest that the neurotoxic mechanism of action of these two antitubulin agents may be different. Therefore, further investigations are required in order to investigate different possible therapeutic approach.