Effects And Mechanism Of Oxaliplatin In Dorsal Root Ganglion Injury

Background and purposeOxaliplatin(OXP)plays an important role in the treatment of metastatic colorectal cancer.Approximately 80-90% of patients may suffer from different degrees of oxaliplatin-induced peripheral neurotoxicity(OIPN).At present,the mechanism of OIPN is unknown and there are no effective prevention measures.Recent studies have confirmed that OXP is mainly accumulated in the Dorsal Root Ganglion(DRG),and the occurrence of OIPN may be directly related to DRG injury.DRG is a primary neuron.To ensure normal function,neuronal cell metabolism,especially protein metabolism,is active.In central and peripheral neuropathy,abnormal protein metabolism is a common pathological basis.Further study of the effect of OXP on DRG protein metabolism may provide a new direction for the prevention and treatment of OIPN.Therefore,this research will investigate the effect of OXP on DRG injury,especially from the perspective of protein metabolism,by looking for differentially expressed proteins,to find a therapeutic target for OIPN,and evaluate the value of imaging changes of OXP DRG injury to OIPN diagnosis.Materials and Methods1.Investigate the effects of OXP on DRG by HE and Nisslite staining,and make statistical analysis on relevant observation indicators.2.Detect and screen the differential proteins in the DRG of the high-dose OXP-treated group and the DRG of the normal control group by the TMT-labeled protein group.3.Verify the expression and activity of CTSB in OXP induced DRG injury by immunohistochemical staining,Western Blot and CTSB activity detection.4.Test the effect of CTSB inhibitor CA074 on DRG treated with OXP by CCK-8 cytotoxicity test,cell morphology observation,Western Blot,CTSB activity test in vitro;behavioral test,HE,Nissl body,immunity histochemical staining,Western Blot,and CTSB activity tests were performed to detect the effects of CTSB inhibitor CA074 on OIPN symptoms and OXP DRG injury in vivo.5.Evaluate the value of imaging changes of OXP DRG injury on the diagnosis of OIPN by magnetic resonance T2WI imaging.Results1.OXP can cause the cytoplasmic density of DRG large-diameter neurons to decrease and contain vacuoles;some cells have lighter nucleus staining,nucleus and nucleoli morphology are fuzzy and irregular;as the cumulative dose of OXP increases.,the diameter of large diameter neurons and the number of Nissl bodies showed a decreasing trend(P <0.05).2.TMT screened a total of 13 differentially expressed proteins,which were involved in different biological processes.Among them,the expression of protein CTSB related to protein metabolism was significantly increased(P <0.05),which was up-regulated 2.53 times in the DRG of the high-dose OXP treatment group.3.As the cumulative dose of OXP increased,the CTSB content and activity in DRG neurons gradually increased(P <0.05).4.CTSB inhibitor CA-074 can inhibit the activity of CTSB in OXP DRG injury in vitro and in vivo(P <0.05),but has no obvious inhibitory effect on the expression of CTSB;CA074 in vivo can partially suppress OIPN symptoms(P <0.05).5.OXP DRG injury can lead to a decrease in DRG signal on T2WI imaging(P <0.05),which has no significant effect on DRG volume;as the cumulative dose of OXP increases,the DRG signal gradually decreases(P <0.05).Conclusions1.OXP can cause pathological damage to DRG neurons,and the degree of damage is positively correlated with the cumulative dose of drugs.In this study,the multi-frequency and multi-dose administration method of OXP successfully constructed the DRG injury model,which can be used in subsequent studies.2.OXP can increase the expression and activity of CTSB in the dorsal root ganglion,and it is positively correlated with the cumulative dose of the drug.3.CTSB inhibitor CA074 can effectively reduce oxaliplatin dorsal root ganglion injury and partially alleviate the symptoms of oxaliplatin peripheral neurotoxicity.CTSB can be used as a potential target for the treatment of peripheral neurotoxicity.4.T2WI imaging can directly reflect the injury of the dorsal root ganglion.The absolute value of DRG signal and the relative signal value of DRG can be used as objective indicators to provide a reference for the diagnosis of oxaliplatin peripheral neurotoxicity.