SRT1720鞘内给药对乳腺癌骨转移大鼠疼痛的影响及其机制

Effect of intrathecal administration of SRT1720 on pain of rats with bone metastases from breast cancer

目的 观察SRT1720鞘内给药对乳腺癌骨转移大鼠疼痛的影响,并探讨其可能的机制。方法 将18只雌性SD大鼠随机分为假手术组、模型组和SRT1720组,每组6只。模型组和SRT1720组均采用胫骨髓腔内注射大鼠乳腺癌MRMT-1细胞悬液的方法建立乳腺癌骨转移疼痛模型,假手术组仅在胫骨髓腔内注射相同体积HBSS缓冲液。建模12 d后,SRT1720组单次鞘内注射SRT1720,模型组与假手术组注射相同体积DMSO+生理盐水(体积比为1∶1)。各组给药后0、1、3、5、7、24 h检测50%缩足阈值(PWT);给药后24 h处死,采用Western blotting法检测脊髓组织SIRT1、p-SIRT1表达,采用ELISA法检测脊髓组织TNF-α表达。结果 与假手术组比较,模型组给药后0、1、3、5、7、24 h的50%PWT均降低,SRT1720组给药后0、24 h的50%PWT均降低(P均<0.05);与模型组同时间点比较,SRT1720组给药后1、3、5、7、24 h的50%PWT均升高(P均<0.05)。与假手术组比较,模型组脊髓组织SIRT1、p-SIRT表达均降低,TNF-α表达升高(P均<0.05);与模型组比较,SRT1720组脊髓组织SIRT1、p-SIRT1表达及p-SIRT1/SIRT1均升高,TNF-α表达降低(P均<0.05)。结论 SRT1720鞘内给药可减轻乳腺癌骨转移大鼠的疼痛,其机制可能与激活脊髓SIRT1活性及抑制炎症反应有关。

Objective To investigate the effect and mechanism of intrathecal administration of SRT1720 on pain of rat models with bone metastases from breast cancer.Methods Eighteen female Sprague-Dawley rats were randomly divided into the sham group,model group and SRT1720 group,with 6 rats in each group.In the model group and SRT1720 group,the bone metastases pain models were established by inoculating the rat breast cancer MRMT-1 cells into the bone marrow cavity,while rats in the Sham group were only injected with the same volume of HBSS buffer into the medullary cavity.At 12 days after inoculation,rats in the SRT1720 group were intrathecally injected with SRT1720,singly,while rats in the model group and sham group were injected with the same volume of DMSO+normal saline(volume ratio of 1∶1).The values of 50%paw withdrawal threshold(PWT)of three groups were detected at 0,1,3,5,7 and 24 hafter SRT1720 injection.After 24-hour treatment,rats were sacrificed and their spinal cord tissues were collected for detecting SIRT1 and p-SIRT1 expression by Western blotting,and TNF-αexpression by ELISA.Results Compared with the sham group,the 50%PWT at 0,1,3,5,7,and 24 h after administration in the model group decreased,and the 50%PWT at 0 and 24 h after administration in the SRT1720 group decreased(all P<0.05);Compared with the model group,50%PWT of the SRT1720 group increased at 1,3,5,7,24 h after administration(all P<0.05).Compared with the sham group,SIRT1 and p-SIRT in the spinal cord tissues of the model group decreased,and TNF-αexpression increased(all P<0.05);compared with the model group,SIRT1,p-SIRT1 expression and p-SIRT1/SIRT1 increased,and TNF-αexpression decreased in the SRT1720 group(all P<0.05).Conclusion Intrathecal administration of SRT1720 alleviates bone metastases pain from breast cancer of rats and the mechanism may be related to the activation of SIRT1 activity and inhibition of inflammatory response in the spinal cord.