• Cristina Meregalli, Ivan Marjanovic, Carla Scali, Laura Monza, Nadia Spinoni, Cristina Galliani, Rinaldo Brivio, Alessia Chiorazzi, Elisa Ballarini, Virginia Rodriguez-Menendez, Valentina Alda Carozzi, Paola Alberti, Giulia Fumagalli, Eleonora Pozzi, Annalisa Canta, Marina Quartu, Chiara Briani, Norberto Oggioni, Paola Marmiroli, and Guido Cavaletti.
• School of Medicine and Surgery, Experimental Neurology Unit and Milan Center for Neuroscience, University of Milano-Bicocca, via Cadore 48, 20900, Monza, MB, Italy. cristina.meregalli@unimib.it.
• J Neuroinflamm. 2018 Aug 21; 15 (1): 232.

BackgroundChemotherapy-induced peripheral neurotoxicity (CIPN) is a severe adverse effect in patients receiving antitumor agents, and no effective treatment is available. Although the mechanisms responsible for the development of CIPN are poorly understood, recent findings make neuroinflammation an attractive target to be investigated, particularly when neuropathic pain is a prominent feature such as after bortezomib administration. The aim of our study was to evaluate the effect of intravenous immunoglobulins (IVIg) delivery in chronic CIPN. The related neuro-immune aspects were investigated in a well-characterized rat model of bortezomib-induced peripheral neurotoxicity (BIPN).MethodsAfter determination of a suitable schedule based on a preliminary pharmacokinetic pilot study, female Wistar rats were treated with IVIg 1 g/kg every 2 weeks. IVIg treatment was started at the beginning of bortezomib administration ("preventive" schedule), or once BIPN was already ensued after 4 weeks of treatment ("therapeutic" schedule). Neurophysiological and behavioral studies were performed to assess the extent of painful peripheral neurotoxicity induced by bortezomib, and these functional assessments were completed by pathologic examination of peripheral nerves and intraepidermal nerve fiber quantification (IENF). The role of the innate immune response in BIPN was investigated by immunochemistry characterization of macrophage infiltration in peripheral nerves.ResultsBoth schedules of IVIg administration were able to significantly reduce bortezomib-induced heat and mechanical allodynia. Although these changes were not evidenced at the neurophysiological examination of peripheral nerves, they behavioral effects were paralleled in the animals treated with the preventive schedule by reduced axonopathy in peripheral nerves and significant protection from loss of IENF. Moreover, IVIg administration was very effective in reducing infiltration in peripheral nerves of macrophages with the M1, pro-inflammatory phenotype.ConclusionOur results suggest a prominent role of neuroinflammation in BIPN and that IVIg might be considered as a possible safe and effective therapeutic option preventing M1 macrophage infiltration. However, since neuropathic pain is frequent also in other CIPN types, it also indicates the need for further investigation in other forms of CIPN.

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