RIP3/MLKL pathway‐regulated necroptosis: A new mechanism of paclitaxel‐induced peripheral neuropathy
Autor: | Shuang Zhao, Huizhou Li, Jiaxin Liu, Xin Liu, Xiuli Wang, Jing Cao, Zhao Li, Dongyang Ma |
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Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Paclitaxel Health Toxicology and Mutagenesis Necroptosis Pharmacology Toxicology Biochemistry Proinflammatory cytokine Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine Animals Protein kinase A Molecular Biology 030102 biochemistry & molecular biology Glial fibrillary acidic protein biology Chemistry Kinase Peripheral Nervous System Diseases General Medicine Rats Allodynia Receptor-Interacting Protein Serine-Threonine Kinases 030220 oncology & carcinogenesis Hyperalgesia biology.protein Molecular Medicine medicine.symptom Protein Kinases Signal Transduction |
Zdroj: | Journal of Biochemical and Molecular Toxicology. 35 |
ISSN: | 1099-0461 1095-6670 |
Popis: | 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. |
Databáze: | OpenAIRE |
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