Oxaliplatin-induced blood brain barrier loosening: a new point of view on chemotherapy-induced neurotoxicity

// Jacopo Junio Valerio Branca 1 , Mario Maresca 2 , Gabriele Morucci 1 , Matteo Becatti 3 , Ferdinando Paternostro 1 , Massimo Gulisano 1 , Carla Ghelardini 2 , Daniela Salvemini 4 , Lorenzo Di Cesare Mannelli 2, * and Alessandra Pacini 1, * 1 Department of Experimental and Clinical Medicine, Anatomy and Histology Section, University of Florence, Florence, Italy 2 Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy 3 Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy 4 Department of Pharmacology and Physiology Saint Louis University, Saint Louis, Missouri, United States * These authors contributed equally to this work Correspondence to: Jacopo Junio Valerio Branca, email: jacopojuniovalerio.branca@unifi.it Alessandra Pacini, email: alessandra.pacini@unifi.it Keywords: blood brain barrier; RBE4 cell line; Oxaliplatin; tight junctions; neuropathic pain Received: February 28, 2018      Accepted: April 02, 2018      Published: May 04, 2018 ABSTRACT Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer. Despite its beneficial effects in tumor reduction, the most prevalent side-effect of oxaliplatin treatment is a chemotherapy-induced neuropathy that frequently forces to discontinue the therapy. Indeed, along with direct damage to peripheral nerves, the chemotherapy-related neurotoxicity involves also the central nervous system (CNS) as demonstrated by pain chronicity and cognitive impairment (also known as chemobrain), a newly described pharmacological side effect. The presence of the blood brain barrier (BBB) is instrumental in preventing the entry of the drug into the CNS; here we tested the hypothesis that oxaliplatin might enter the endothelial cells of the BBB vessels and trigger a signaling pathway that induce the disassembly of the tight junctions, the critical components of the BBB integrity. By using a rat brain endothelial cell line (RBE4) we investigated the signaling pathway that ensued the entry of oxaliplatin within the cell. We found that the administration of 10 μM oxaliplatin for 8 and 16 h induced alterations of the tight junction (TJs) proteins zonula occludens-1 (ZO-1) and of F-actin, thus highlighting BBB alteration. Furthermore, we reported that intracellular oxaliplatin rapidly induced increased levels of reactive oxygen species and endoplasmic reticulum stress, assessed by the evaluation of glucose-regulated protein GRP78 expression levels. These events were accompanied by activation of caspase-3 that led to extracellular ATP release. These findings suggested a possible novel mechanism of action for oxaliplatin toxicity that could explain, at least in part, the chemotherapy-related central effects.