Pathological And Neurobiological Study On The Toxicity Of Peripheral Nerve System Induced By Oxaliplatin

Objective: Oxaliplatin is a third-genernation platinum-based chemotherapeutic agent and play an important role in the metastatic colorectal treatment. The aim of this study was to investigate whether the pathological changes of peripheral neurotoxicity induced by oxaliplatin depended on the dose administered and on the recovery time. This experiment also investigate the changes of nerve growth factor expression during the oxaliplatin treatment and the relationship between the NGF expression and the histologic toxicity of dorsal root ganglia which is the primary target of peripheral neurotoxicity induced by oxaliplatin. Methods: The experiment was divided into two parts. Group A: 96 wistar female rats were divided into two groups: treated group and control group. These two groups were also divided into 12 subgroups respectively. These 12 groups represented 12 time points. Treated groups were given oxaliplatin 20mg/kg. Left L4-5 dorsal root ganglia and sciatic nerve of all rats were dissected out at different time points. Group B: 24 wistar female rats were divided into 6 subgroups including 1 control group and 5 treated groups. Treated groups were given different dose of oxaliplatin ( 1mg/kg﹑5mg/kg,10mg/kg,20mg/kg ,30mg/kg ) and Left L_4-5 dorsal root ganglia and sciatic nerve of all rats were gotten at 24 hours after oxalipaltin treatment. DRG sensory neurons and sciatic nerves of all rats were studied by the light microscopy and transmission electron microscopy technique to define the pathological changes at various time points when treated with a single dose of oxaliplatin and at 24 hours after given single doses of oxaliplatin. The expression of NGF in DRG were detected by immunohistochemistry. DRG sensory neurons and the expression of NGF were analyzed by Digital Medical Image Analysis System to determine the morphological changes of DRG and the expression changes of NGF. Results: The neuropathological examination evidenced shrinkage of DRG soma, nucleus, and nucleolus were shown in the treated rats. Concintration of cytoplasm and edema of mitochondrion were also observed in treated groups. All these changes were evident at 24～48 hours and almost completely recovered in 5 weeks. The area of DRG soma and nucleus all showed a linear trend of dose-dependence at 24 hours (r²=0.9569,P=0.0007; r²=0.9826,P=0.0001). Nucleolus area showed a non-linear dependence on dose at 24 hours (r²=0.9842). Sciatic nerve underwent mild myelinic degeneration at 24 hours after treatment and also most recovered in 5 weeks. Edema of mitochondrion and reduced quantity of microfilaments and microtubules were observed in the nerve filbers of treated groups. The down-regulation of NGF expression was evident at 24-48 hours and completely recovered in 5 weeks. The changes of NGF expression also showed a dependence on dose. Conclusions: In the period of oxaliplatin treatment, pathological changes of periphereal nerve system were mild. DRG was the main...