Mn and Mg protect against the oxaliplatindependent NVU impairment

Oxaliplatin is a well-known chemotherapeutic drug largely used for metastatic colorectal cancer. Even though oxaliplatin has showed beneficial effects in tumour reduction, it is able to induce neuropathic pain, thus leading for dose reduction and therapy discontinuation. Recently, it has been demonstrated the oxaliplatin- dependent alteration in a blood-brain barrier (BBB) in vitro model that may, at least in part, explain the mechanism by which oxaliplatin treatment triggers neuropathic pain. Also, glial cells, an integral part of the so-called neurovascular unit (NVU), have a pivotal role in eliciting neuropathy. However, very little is known how counteract these deleterious effects. We postulate that the antioxidant properties of manganese (MnCl2) and magnesium chloride (MgCl2) can protect glial compartment from oxaliplatin-induced damage. In order to validate our hypothesis, we performed molecular and morphological assays to monitor the effectiveness of MnCl2 and MgCl2 during oxaliplatin treatment on different cell lines. Our data show the oxaliplatin-dependent effects on ROS production, endoplasmic reticulum stress, and caspase-3 activation. On the contrary, both MnCl2 and MgCl2 treatment are able to reduce oxidative and endoplasmic reticulum stress, as well as to retrieve caspase-3 activation. Moreover, BBB tight junction dysfunction and glial markers were analysed by immunofluorescent analysis. In conclusion, our results showed the ability of MnCl2 MgCl2 to oxidative and ER stress induced by oxaliplatin, suggesting that MnCl2 and MgCl2 could be a new tool to counteract the chemotherapy-dependent NVU alterations.