A major dose-limiting side effect of docetaxel chemotherapy is peripheral neuropathy. Patients’ symptoms include pain, numbness, tingling and burning sensations, and motor weakness in the extremities. The molecular mechanism is currently not understood, and there are no treatments available. Previously, we have shown an association between neuropathy symptoms of patients treated with paclitaxel and the plasma levels of neurotoxic sphingolipids, the 1-deoxysphingolipids (1-deoxySL) (Kramer et al, FASEB J, 2015). 1-DeoxySL are produced when the first enzyme of the sphingolipid biosynthetic pathway, serine palmitoyltransferase (SPT), uses L-alanine as a substrate instead of its canonical amino acid substrate, L-serine. In the current investigation, we tested whether 1-deoxySL accumulate in the nervous system following systemic docetaxel treatment in mice. In dorsal root ganglia (DRG), we observed that docetaxel (45 mg/kg cumulative dose) significantly elevated the levels of 1-deoxySL and L-serine-derived ceramides, but not sphingosine-1-phosphate (S1P). S1P is a bioactive sphingolipid and a ligand for specific G-protein-coupled receptors. In the sciatic nerve, docetaxel decreased 1-deoxySL and ceramides. Moreover, we show that in primary DRG cultures, 1-deoxysphingosine produced neurite swellings that could be reversed with S1P. Our results demonstrate that docetaxel chemotherapy up-regulates sphingolipid metabolism in sensory neurons, leading to the accumulation of neurotoxic 1-deoxySL. We suggest that the neurotoxic effects of 1-deoxySL on axons can be reversed with S1P. (Figure presented.).
|Number of pages||11|
|Journal||Journal of Neurochemistry|
|State||Published - Sep 1 2020|
Bibliographical noteFunding Information:
We thank the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky (Lexington, KY, USA) for the support of this work and the Lipidomics core facility at the Medical University of South Carolina (Charleston, SC, USA) for the mass spectrometry measurements of sphingolipids. This work was in part supported by NIH grants R01NS62306 to BKT, R01AG034389 to EB, R56AG064234 to EB, and Department of Veteran Affairs grant I01 BX003643 to EB. The authors declare no conflicts of interest. All experiments were conducted in compliance with the ARRIVE guidelines.
© 2020 International Society for Neurochemistry
- Docetaxel-induced peripheral neuropathy
- Serine palmitoyltransferase
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience