Role of Schwann cell-derived Exosomes in Cisplatin-induced Hyperalgesia

Abstract

Painful peripheral neuropathy is a common dose-limiting side effect associated with cisplatin treatment. Cisplatin is unable to cross the blood-brain barrier, and its neurotoxicity is limited to the peripheral nervous system (PNS). In the PNS, Schwann cells are an essential component supporting dorsal root ganglion (DRG) neuron viability, and impairments in Schwann cell biology contribute to cisplatin-induced painful neuropathy. We explored the role of Schwann cell-derived exosomes in the development of cisplatin-induced hyperalgesia. Consistent with our previous reports, daily injection of cisplatin (1 mg/kg, i.p.) for 7 days produced mechanical hyperalgesia in C3H/HeN mice. To investigate the impact of exosome signaling in the development of cisplatin-induced hyperalgesia, exosomes isolated from the sciatic nerves of cisplatin-treated mice were injected intrathecally into naïve mice for 5 consecutive days (7 g of total protein/10 l, i.t.). Mechanical hyperalgesia was observed after the second injection of exosomes, mimicking the effect of cisplatin alone and supporting the involvement of integrated exosome signaling in hyperalgesia produced by cisplatin. Intrathecal administration of Schwann cell-derived exosomes activated microglia, and analysis of exosomal content indicated mediators of neuronal sensitization at the central level. Collectively, our results indicate that Schwann cells affected by cisplatin contribute to mechanical hyperalgesia and exosomes are an important signaling mediator for glia-neuronal communication.