Satellite Glial Cells in Chemotherapy Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect caused by many of the most commonly used chemotherapeutic agents, including anti-tubulins (paclitaxel, PTX) and platinum derivatives (cisplatin, CDDP). Due to incomplete understanding of the molecular mechanisms of CIPN, to date no effective therapy is available. Sensory neurons into dorsal root ganglia (DRG) have been investigated as principal targets of neurotoxicity so far. In this study, we focus on a possible novel target of CIPN, investigating the changes of satellite glial cells (SGCs) in the DRG and their crosstalk with neurons following repeated administration of PTX and CDDP in rats. Morpho-functional analyses were performed to verify the features of CIPN. Qualitative and quantitative immunohistochemistry, 3Dimmunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that after 4 weeks of PTX, but not CDDP treatment, SGCs were strongly activated. A similar activation remained after 4 weeks of follow up, when the painful component of neuropathy, but not the nerve damage, was resolved. In addition, nonphysiological connections between SGCs and/or SGC-neuron were evident in PTX rats: we observed activated SGCs surrounding different adjacent neurons and an increase in the intimate contact between SGCs and their associated neurons where a complex and peculiar pattern of glial cytoplasmic projections was present. Moreover, PTX increased the expression of Connexin43 with perineuronal localization and the expression of the adhesion molecule L1-CAM in the cytoplasm and plasma membrane of neurons. We conclude that SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for CIPN treatment and prevention.