Microglial polarization and necroptosis in the spinal cord

Paclitaxel (PTX) is a widely used chemotherapeutic agent for the treatment of several types of tumors. However, PTX-induced peripheral neuropathy (PIPN) is a common adverse effect of long-term PTX use that significantly impairs quality of life. Necroptosis has been implicated in various neurodegenerative disorders, with necroptosis of dorsal root ganglion (DRG) neurons specifically being reported to contribute to the pathogenesis of PIPN. Therefore, the present study aims to investigate the effect of spinal neuronal necroptosis on PIPN, and to explore the potential role of microglia polarization on necroptosis. We established rat models of PIPN via quartic PTX administration on alternate days (accumulated dose: 8mg/kg). PTX caused evident neuronal necroptosis and upregulated the expression of receptor-interacting protein kinase (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the spinal dorsal horn, and a necroptosis pathway inhibitor, necrostatin-1 (Nec-1), was able to inhibit these effects. The regulatory impact of microglial polarization on spinal necroptosis was elucidated by administering minocycline to specifically inhibit PTX-induced M1 polarization of spinal microglia caused by PTX. We observed a significant inhibitory effect of minocycline on PTX-induced necroptosis in spinal cord cells, as evidenced by the downregulation of RIP3 and MLKL expression, and suppression of TNF-α and IL-β production. Additionally, minocycline improved hyperalgesia symptoms in PIPN rats. Overall, this study provides evidence that PTX-induced polarization of spinal microglia contributes to RIP3/MLKL-regulated necroptosis, and is implicated in the development of PIPN. These findings suggest a potential novel therapeutic target for the prevention and treatment of neuropathic pain.