RIP3/MLKL pathway-regulated necroptosis: A new mechanism of paclitaxel-induced peripheral neuropathy

J Biochem Mol Toxicol. 2021 Aug;35(8):e22834. doi: 10.1002/jbt.22834. Epub 2021 May 30.

Abstract

Paclitaxel (PTX) chemotherapy treatment often leads to neuropathic pain, which is resistant to available analgesic treatments. Death of cells and neuroinflammatory response are associated with PTX-induced peripheral neuropathy (PIPN). Necroptosis is a form of regulated necrotic cell death that accompanies strong inflammatory response. It is mediated by receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like protein (MLKL), which contribute to the pathogenesis of several neurodegenerative diseases. Nevertheless, the role of necroptosis in PIPN remains unexplored. The aim of this study was to investigate the role of necroptosis in PIPN using its antagonists (necrostatin-1 and Nec-1). The quartic PTX administration (accumulated dose: 8 mg/kg, ip) in rats induced robust hyperalgesia and allodynia with significant cell necrosis and an increase in proinflammatory cytokines in the dorsal root ganglion (DRG). PTX application also increased RIP3 and MLKL protein levels in DRG, which were primarily in neurons. Moreover, it also promoted satellite glial cells (SGCs) activation, as assayed by glial fibrillary acidic protein (GFAP) upregulation. All these PTX-induced changes were prevented by the Nec-1 treatment. When taken together, the present study indicated that RIP3/MLKL pathway-regulated neuronal necroptosis, which promoted an inflammatory cascade reaction in DRG, might be a new mechanism of PIPN.

Keywords: hyperalgesia; necroptosis; necrostatin-1; paclitaxel; peripheral neuropathy.

MeSH terms

  • Animals
  • Male
  • Necroptosis / drug effects*
  • Paclitaxel / adverse effects*
  • Paclitaxel / pharmacology
  • Peripheral Nervous System Diseases* / chemically induced
  • Peripheral Nervous System Diseases* / metabolism
  • Protein Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / drug effects*

Substances

  • MLKL protein, rat
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, rat
  • Paclitaxel