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               Neuroprotective  effects  of  Lauraceae-derived  sesquiterpenes  against

               oxaliplatin-induced peripheral neuropathy in ND7/23 cells


                                                                       2
                                       #,1
                                                                                                    ,2
               Chao-Han Tu (杜兆涵),  Hsun-Shuo Chang (張訓碩),  Horng-Huey Ko (柯宏慧),*  Yih-
               Fung Chen (陳宜芳)*
                                     ,3

               1  Department of Medical Laboratory Science and Biotechnology, Collage of Health Sciences,
                 Kaohsiung Medical University, Kaohsiung, Taiwan
               2  School of Pharmacy, Collage of Pharmacy, Kaohsiung Medical University, Kaohsiung,
                 Taiwan
               3  Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
               * Email: hhko@kmu.edu.tw; yihfungchen@kmu.edu.tw

               Abstract
                  Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of cancer
               treatment  that  can  severely  impair  the  quality  of  life  of  cancer  survivors.  Among
               chemotherapeutic  agents,  oxaliplatin,  a  third-generation  platinum  compound,  remains  a
               standard treatment for advanced colorectal cancer but is also a major cause of CIPN. In severe
               cases,  oxaliplatin-induced  peripheral  neuropathy  (OIPN)  may  lead  to  early  treatment
               discontinuation.  Currently,  no  FDA-approved  drugs  are  available  for  the  prevention  or
               treatment  of  OIPN.  Previous  studies  suggest  that  chemotherapeutic  agents  accumulate  in
               peripheral  sensory  nerves,  particularly  in  dorsal  root  ganglion  (DRG)  neurons,  leading  to
               oxidative stress and reduced cell viability. In this study, we investigated sesquiterpenes from
               Lauraceae plants,  known for their structural  diversity  and biological  activities, as  potential
               neuroprotective  agents.  Twelve  candidates  (compounds  1-12)  were  selected  based  on
               antioxidant-related  scaffolds.  ND7/23  cells,  an  immortalized  DRG  neuronal  cell  line  that
               closely  mimics  primary  cultured  sensory  DRG  neurons,  were  used  to  establish  an  in  vitro
               screening platform for OIPN. Exposure of ND7/23 cells to oxaliplatin (1-100 μM, 48 h) induced
               a dose-dependent decrease in cell viability and an increase in intracellular reactive oxygen
               species (ROS) levels. The candidate compounds were first tested for their safe concentration
               range,  followed  by  neuroprotection  evaluation  at  their  respective  non-toxic  concentrations.
               Among the twelve compounds, compounds 2, 5, 9, and 11 (1-10 μM) significantly attenuated
               oxaliplatin-induced  cell  death  and  ROS  accumulation.  These  findings  highlight  the
               neuroprotective potential of sesquiterpene compounds against OIPN.

               Keywords:  Chemotherapy-induced  peripheral  neuropathy  (CIPN);  Oxaliplatin;  Dorsal  root
                           ganglion (DRG); Neurotoxicity; Reactive oxygen species (ROS); Sesquiterpene;
                           Lauraceae
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