• Di Cesare MannelliLorenzoLDipartimento di Neuroscienze, Psicologia, Scienze del Farmaco e Salute del Bambino (NEUROFARBA), Sezione di Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini, 6, Firenze 50139, Italy., Matteo Zanardelli, Ida Landini, Alessandra Pacini, Carla Ghelardini, Enrico Mini, Andrea Bencini, Barbara Valtancoli, and Paola Failli.
• Dipartimento di Neuroscienze, Psicologia, Scienze del Farmaco e Salute del Bambino (NEUROFARBA), Sezione di Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini, 6, Firenze 50139, Italy.
• Free Radic. Biol. Med. 2016 Apr 1; 93: 67-76.

BackgroundOne of the most discomfortable dose-limiting adverse reactions of effective drugs for the treatment of solid tumors is a peripheral neuropathy which is the main reason for dose reduction and discontinuation of the therapy. We identified oxidative stress as one target of oxaliplatin toxicity in the search of possible adjuvant therapies to prevent neuropathy and alleviate pain. Therefore, we studied an effective SOD mimetic compound, MnL4, as a possible adjuvant treatment in in vitro cellular cultures and in vivo on a rat model of oxaliplatin-induced neuropathy.Methods And ResultsAll rat manipulations were carried out according to the European Community guidelines for animal care. We performed experiments on SH-SY5Y, HT-29 and primary cortical rat astrocytes. Incubation with 100 µM oxaliplatin increased superoxide anion production and caspase 3/7 activity in the neuronal cell line SH-SY5Y and cortical astrocytes. MnL4 (10 µM) significantly reduced the increase in superoxide anion in both cell types, but prevented caspase 3/7 activity only in astrocytes. MnL4 reduced lipid peroxidation induced by oxaliplatin and normalized the intracellular calcium signal evoked by ATP and acetylcholine in astrocytes, preincubated with oxaliplatin. MnL4 did not interfere with the concentration- and time-dependent cytotoxic effects of oxaliplatin on the cancer cell lines HT-29 and LoVo. In vivo MnL4 reduced the response at mechanical noxious and mechanical and thermal non-noxious stimuli in oxaliplatin treated animals. Rat rota-rod performances were improved.ConclusionSince MnL4 exerts its beneficial effects without interfering with the anticancer activity of oxaliplatin, it could be proposed as adjuvant to prevent and reduce oxaliplatin induced neuropathy.Copyright © 2016 Elsevier Inc. All rights reserved.

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