Morphometrical characterization of DRG alterations induced by cisplatin and bortezomib in several mice models

Cisplatin (CDDP) and Bortezomib (BTZ) are two antineoplastic drugs commonly used against different solid tumors and multiple myeloma, respectively. Although their efficacy, the clinical employment of these chemoterapeutics is associated with a severe neurotoxicity that represents the dose-limiting factor in therapy. Previous well established rat models evidenced the toxic effects of CDDP particularly on the dorsal root ganglia (DRG) sensory neurons that are smaller in the somatic, nuclear and nucleolar sizes. To investigate the role of CDDP and BTZ on the peripheral nervous system we used three mice models: female Balb/c were treated with CDDP 4mg/Kg (ip, 2qwx4) and with BTZ 0,8 mg/Kg (iv, 2qwx4), while female Hola Hsd NuNu and CD1 mice were treated with CDDP 4mg/Kg (ip 2qwx4 followed by 2 weeks of follow-up) and with BTZ 0,8 mg/Kg (iv, 2qwx6). The aim of this study was to perform a morphometrical quantification of cisplatin and bortezomib-induced toxic effects on the DRG neurons in the different mice strains. Three L4-L5 DRG/animals were collected, fixed and resin-embedded; 1 micro-sections stained with toluidine blu were analyzed with a computer-assisted image analyzer (Image J NIH sotware). In randomly selected sections the somatic, nuclear and nucleolar sizes of DRG sensory neurons were measured on at least 200 DRG neurons/animal. The morphometrical analysis of DRG showed that the administration of CDDP affects neurons causing a decrease in the size of somatic and nucleolar area in the Balb/c and CD1mice while the Nu/Nu strain showed only a decrease in the nuclear area. By contrast, the administration of BTZ induced an increase in the size of somatic, nuclear and nucleolar area in the Balb/c mice while only nucleolar area was increased in Nu/Nu and CD1 mice. The results obtained with the administration of CDDP seems to confirm the previous studies in rat, showing the toxic role of CDDP on neurons of DRG. Since the BTZ-induced increase in the cellular sizes seems to be unespected, it could be explained by a selective damage of the subpopulation of small-size neurons. This hypothesys needs to be confirmed by a immunohistochemical study of the distribution of the different neuronal subpopulations in the DRG of naïve and BTZ-treated animals.