奥沙利铂（Oxa）为第三代广谱抗肿瘤铂类药物，但其广泛而严重的外周神经毒性限制其应用，且目前无有效对策。由于Oxa被动透过性差，需转运体介导进行跨细胞转运。Oxa主要损伤背根神经节（DRG），而DRG上高表达的有机阳离子转运体2（OCT2）、多药耐药蛋白(MRP) 等可能在Oxa的摄取和外排中发挥重要作用。我们前期研究发现，延胡索乙素 (THP) 对OCT2具有选择性抑制作用，能明显降低Oxa在MDCK-hOCT2的细胞积聚和毒性，亦能明显减轻Oxa引起小鼠对冷刺激的敏感性。我们推测，THP可能通过选择性抑制DRG神经元上OCT2介导的Oxa摄取，减少Oxa蓄积，从而减轻Oxa神经毒性。本项目拟应用多种转基因细胞模型、原代细胞、小鼠、荷瘤裸小鼠等模型，系统阐明THP对OCT2的选择性抑制，及其减轻Oxa神经毒性而不减弱其抗肿瘤作用的机制，为THP用于降低Oxa神经毒性提供依据。

Oxaliplatin (Oxa) is the third-generation antitumor platinum drugs and widely used, however widespread and serious peripheral neurotoxicity limits its clinical application. Due to the poor passive penetration of Oxa, organic cation transporter 2 (OCT2), multidrug resistance protein (MRP) and other transporters highly expressed in DRG may play important roles in the process of its transport of Oxa. Oxa can induce apoptosis of dorsal root ganglion (DRG), however, currently it has not yet been found an effective drug in clinic, which has the potential to prevent Oxa-induced neurotoxicity in patients, mainly based on the inhibition of accumulation of Oxa in DRG. Our previous work demonstrated that tetrahydropalmatine (THP) had significant inhibitory effect on OCT2, which protected against severe Oxa-induced cytoxicity on MDCK-hOCT2 cells in a concentration-dependent manner, and could significantly reduce the sensitivity of mice to cold stimulation induced by Oxa. Therefore, we proposed that THP co-administrated with Oxa, might have an effect on Oxa accumulation via OCT2, then reduces Oxa-induced neurotoxicity. To confirm the hypothesis, the transgenic cells, primary cultured DRG cells, C57 mouse and nude mouse bearing the tumor would be used to investigate the molecular mechanism in the protective effect of THP on Oxa-induced neurotoxicity based on OCT2-mediated accumulation of Oxa in DRG. If the results as our expect，the concomitant-administration of THP was revealed to be a useful strategy preventing Oxa-induced neurotoxicity without impairing its anticancer efficacy. The results offer the scientific basis for the future clinical THP as a specific modifier of Oxa-induced neurotoxicity.