| Objective: Oxaliplatin is a third-generation platinum-based chemotherapeutic agent and play an important role in the colorectal cancer and gartric carcinoma treatment. Neurotoxicity is its dose-limiting symptom. In humans, two different types of neurological symptoms occur during oxaliplatin treatment. Disabling peripheral neuropathy has a significant negative impact on quality of life and interrupt the chemotherapy. Accordingly, potential neuroprotective agents are to be investigated. Glutathione is a hopeful chemoprotectant to ameliorate the toxicity associated with platinum-based chemotherapeutic agent. But there exist objection whether or not neuroprotective effect of GSH in clinical neurotoxicity of cisplatin. There have been few studies that neuroprotective effect of GSH in experiment of neurotoxicity of oxalplatin. The aim of this study was to investigate whether the pathological changes of peripheral neurotoxicity induced by oxlaiplatin depended on recovery time. This experiment also initially investigate the potential neuroprotective effect of GSH in dorsal root ganglion neurons in vivo from pathology and neurobiology . Methods: 120 healthy male Wistar rats were randomly divided into three groups (n=40 in each): control group were given 5%glucose 30ml/kg and study group were given single intraperitoneal doses of oxaliplatin20mg/kg and in combination with reduced glutathione 500mg/kg. These three groups were also divided into 10 subgroups respectively. These 10 groups represented 10 time points from 0 hours,24 hours,48 hours,1,2,3,4,5,6 to 7 weeks. Left L4-5 dorsal root ganglia and sciatic nerves of all rats were dissected out at different points. 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 a single dose of GSH before intraperitioneal oxaliplatin. The expression of NGF in DRG was detected by immunohistochemistry. DRG sensory neurons and the expression of NGF were analyzed by Digital Medical Image Analysis System to determine the morphologhical changes of DRG and the expression of NGF.Results: 1. Protection of the general toxicity of oxaliplatin. GSH group of slowly acts, reduction foraging, diarrhea, bleeding of the skin mucosa general toxicity rates significantly lower than oxaliplatin group. Medication 1-7weeks, The weight of after treated rats ,compared with the control group, has a statistically significant difference in 1,2,3,4,5,6,7 weeks(P<0.0001).Oxaliplatin plus GSH compared with the control group has significant difference in 1,2-week( P <0.05); and has significant difference compared with the group of rats were given single intraperitoneal doses of oxaliplatin(P<0.05)in 1-7 weeks. 2. The results of neuron morphology. In the period of oxaliplatin treatment, DRG was the main target of the peripheral neurotoxicity. The nucleolus showed the most prominent pathological changes. The neuropathological examination evidenced shrinkage of DRG soma, nucleus, and nucleolus were shown in the treated rats. All these changes were evident at 48 hours and almost completely recovered in 7 weeks. All these changes of oxaliplatin plus GSH in rats minor oxaliplatin group in 24-48hours, neuronal cell bodies in the cytoplasm and nuclei and nucleoli area was statistically significant differences with the control group( P <0.05). The morphological changes gradually improve after the first week. The area of cellular, nucleus and nucleoli was statistically significant difference compared with the control group (P<0.05). It returned to be normal in 7 weeks. The area of cellular, nucleus and nucleoli of GSH plus oxaliplatin group in rats was no significant difference compared with the oxaliplatin group in 1,2days and 1 week, and the difference was statistically significant compared with the control group (P<0.05); After two weeks was no significant difference compared with the oxaliplatin group (P>0.05) 3. The effect of NGF expression: The NGF expression was evident at 24-48hours and completely recovered in 6 weeks. GSH plus oxaliplatin group was down-rising trend, however, there was no significant difference between the control group after 1 weeks(P>0.05).Conclusion: GSH reduces the toxicity induced by oxaliplatin. The toxicity showed a recovery trend and need long time. GSH maybe reduce the oxaliplatin-induced abnormal of changes of neurons of DRG. NGF expression of plus GSH was markedly higher than the control group was not protected.
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