脊髓背角星形胶质细胞和pCREB在DREAMsiRNA介导的CCI大鼠疼痛基因治疗中的作用
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摘要
目的:探讨慢病毒介导的siRNA沉默DREAM在坐骨神经慢性压迫(chronic constriction injury of the sciatic nerve,CCI)大鼠疼痛基因治疗中的应用;观察脊髓背角星形胶质细胞(astrocyte,Ast)活性在DREAM基因RNA干扰(RNA interference,RNAi)前后的变化;观察pCREB在脊髓背角的总体表达和Ast内的含量变化。进一步了解脊髓背角Ast及pCREB在DREAMsiRNA介导的CCI大鼠疼痛基因治疗中的作用。
方法:选择健康雄性SD大鼠24只,随机分为四组(n=6):即RNAi组、NS组、blank vector组和sham组,造模前1d测定基础痛阈(包括PWTL和PWMT),并于CCI后第7-14d(即T7-T14),每天测定1次。于CCI后第8天(T8)开始经微导管分别注入pKCSHR-Puro/GFP-DREAM慢病毒(1×10~9 IU/ml)5μl+NS 5μl或blank vector 5μl+NS5μl或NS10μl,连续注射7d。于CCI后第15d,取L_(4-5)脊髓节段,石蜡包埋、切片,于荧光显微镜下观察绿色荧光蛋白(GFP)、脊髓背角胶质原纤维酸性蛋白(green fluorescent protein,GFAP)、脊髓背角磷酸化的cAMP反应元件结合蛋白(phosphorylation of cyclic AMP responseelement binding protein,pCREB)的表达。
结果:1.大鼠痛阈的变化:各组基础痛阈比较无统计学意义(p＞0.05);PWTL:左后肢PWTL:RNAi组的T7-T10及T12、sham组的T7-T10、blank vector组及NS组的T7-T14均低于基础痛阈(P＜0.05或P＜0.01);RNAi组的T10、T11、T13及T14均高于该组T7(P＜0.01);blank vector组及NS组的T9-T14均低于同组T7水平(P＜0.05或P＜0.01);blank vector组及NS组的T13和T14分别低于sham组相应时点的阈值(P＜0.05);而RNAi组的T11、T13、T14则分别高于blankvector组和NS组相应时点的阈值(P＜0.05);右后肢PWTL:不同时间点各组间比较,差异无统计学意义(p＞0.05)。PWMT:左后肢PWMT:各组T7-T14均低于基础痛阈(P＜0.05或P＜0.01);RNAi组的T8(P＜0.05)、blank vector组和NS组的T8、T12-T14均低于sham组相应时点的阈值(P＜0.05或P＜0.01);RNAi组的T14高于sham组(P＜0.01);RNAi组的T12-T14分别高于blank vector组和NS组的相应时点的阈值(P＜0.05或P＜0.01);右后肢PWMT:不同时间点各组间比较,差异无统计学意义(P＞0.05)。
2.脊髓背角GFP表达:CCI后14d时,RNAi组脊髓背角神经细胞中GFP表达阳性,blank vector组无GFP的表达,与其余两组相同。
3.脊髓背角GFAP平均荧光强度:blank vector组和NS组最高,且两者比较无统计学意义(P＞0.05);RNAi组与sham组相似(P＞0.05),且均低于以上两组(P＜0.01)。
4.脊髓背角pCREB平均荧光强度:RNAi组CCI后14d时脊髓背角pCREB平均荧光强度明显弱于blank vector组和NS组(P＜0.01),但强于sham组(P＜0.05)。
5.脊髓背角Ast内pCREB平均荧光强度:RNAi组CCI后14d时脊髓背角Ast内pCREB平均荧光强度明显弱于blank vector组和NS组(P＜0.01),但与sham组无差异(P＞0.05)。
结论:1.连续鞘内注射pKCSHR-Puro/GFP-DREAM慢病毒可以明显改善CCI大鼠的痛行为。
2.DREAM基因下调可明显抑制外周神经伤害性刺激诱发的脊髓背角Ast的活化。
3.DREAM基因下调可显著抑制pCREB在脊髓背角的总体表达和Ast内的表达。
4.脊髓背角Ast的活性降低和脊髓背角pCREB的低表达可能在DREAM基因沉默治疗CCI大鼠疼痛中发挥重要作用。
Objective: To detect the application of DREAM silencing through siRNA mediated by lentiviral vector in gene therapy of rats neuropathic pain due to chronic constriction injury of the sciatic nerve (CCI), and to observe the changes of astrocyte activity and phosphorylation of cyclic AMP response element binding protein (pCREB) under the control of RNA interference(RNAi). And to find out the roles of astrocyte activity and pCREB in dorsal horn in gene therapy of neuropathic pain of rats suffered from CCI mediated by DREAM siRNA.
Method: To select 24 rats which were male and healthy, then to divide them randomly into 4 groups(n=6 each), that is, Group RNAi, Group blank vector, Group NS and Group sham. To measure the basic pain threshold before building the model(TO), including paw withdraw thermal latency(PWTL) and paw withdraw mechanical threshold(PWMT), then to repeat the operations once a day until 14th day(T14) after CCI. And we had continuously given pKCSHR-Puro/GFP- DREAM- LV (1×10~9 IU/ml) 5μl + NS 5μl or blank vector 5μl+ NS5μl or NS 10μl by intrathecal injection once a day from 8th day after CCI(T8) to 14th day(T14). At last, we took out the spinal cords(L4-5) and made them into paraffin sections, then through immunofluorescence method, we could observe the expressions of green fluorescent protein(GFP), glial fibrillary acidic protein (GFAP) and pCREB.
Result: Pain threshold: there were no differences among 4 groups with basic pain threshold(P>0.05); PWTL of left paw on T7-T10 and T12 in Group RNAi and T7-T10 in Group sham, and on T7-T14 in Group blank vector and NS were much lower than the respective basic pain threshold(P<0.05 or P<0.01); and those on T10、T11、T13 and T14 in Group RNAi were much higher than that on T7 in the group (P<0.01); And those on T9-T14 in blank vector and NS were much lower(P<0.05 or P<0.01 vs T7); PWTL of left paw on T13-T14 in Group blank vector and Group NS were lower than that in Group sham; and PWTL of left paw on T11,T13 and T14 in Group RNAi were higher than those in Group blank vector and NS (P<0.05). There were no differences among 4 groups with PWTL of right paw on all points(P>0.05). PWMT of left paw: all values noting post-CCI were lower than the level of preoperation. T8 in Group RNAi, T8 and T12-T14 in Group blank vector and Group NS were much lower than those on each point in Group sham(P<0.05 or P<0.01). T14 in Group RNAi was higher than the Group sham's(P<0.01). And T12-T14 in Group RNAi were also higher than that in Group blank vector and NS(P<0.05 or P<0.01). And the case with PWMT of right paw was the same as PWTL of right paw.
GFP: positive expression was only observed in dorsal horn in Group RNAi, and dark was in the views of other groups.
GFAP(average of fluorescence intensity): Group blank vector and Group NS were the highest. Also Group RNAi and Group sham were similar with each other(P>0.05), and both of which were lower than the groups above(P<0.01).
pCREB(average of fluorescence intensity) in dorsal horn: Group RNAi was significantly reduced(P<0.01 vs Group blank vector and NS), but higher than Group sham (P<0.05).
pCREB(average of fluorescence intensity) in astrocytes of dorsal horn: Group blank vector and Group NS were the highest. Also Group RNAi and Group sham were similar with each other(P>0.05), and both of which were lower than the groups above(P<0.01).
Conclusion: 1. The continuous-intrathecal injection of pKCSHR-Puro/GFP-DREAM-LV could evidently relieve pain of rats suffered from CCI in behavioristics.
2.The low expression of DREAM could inhibit the activation of astrocyte in dorsal horn due to nociceptive stimulus with sciatic nerve.
3.The low expression of DREAM could inhibit the total expression of pCREB in dorsal horn, especially in astrocyte.
4.The inhibition of astrocyte's activating and the expression of pCREB in dorsal horn may play an important part in gene therapy of rats with neuropathic pain through DREAM siRNA.
方法:选择健康雄性SD大鼠24只,随机分为四组(n=6):即RNAi组、NS组、blank vector组和sham组,造模前1d测定基础痛阈(包括PWTL和PWMT),并于CCI后第7-14d(即T7-T14),每天测定1次。于CCI后第8天(T8)开始经微导管分别注入pKCSHR-Puro/GFP-DREAM慢病毒(1×10~9 IU/ml)5μl+NS 5μl或blank vector 5μl+NS5μl或NS10μl,连续注射7d。于CCI后第15d,取L_(4-5)脊髓节段,石蜡包埋、切片,于荧光显微镜下观察绿色荧光蛋白(GFP)、脊髓背角胶质原纤维酸性蛋白(green fluorescent protein,GFAP)、脊髓背角磷酸化的cAMP反应元件结合蛋白(phosphorylation of cyclic AMP responseelement binding protein,pCREB)的表达。
结果:1.大鼠痛阈的变化:各组基础痛阈比较无统计学意义(p＞0.05);PWTL:左后肢PWTL:RNAi组的T7-T10及T12、sham组的T7-T10、blank vector组及NS组的T7-T14均低于基础痛阈(P＜0.05或P＜0.01);RNAi组的T10、T11、T13及T14均高于该组T7(P＜0.01);blank vector组及NS组的T9-T14均低于同组T7水平(P＜0.05或P＜0.01);blank vector组及NS组的T13和T14分别低于sham组相应时点的阈值(P＜0.05);而RNAi组的T11、T13、T14则分别高于blankvector组和NS组相应时点的阈值(P＜0.05);右后肢PWTL:不同时间点各组间比较,差异无统计学意义(p＞0.05)。PWMT:左后肢PWMT:各组T7-T14均低于基础痛阈(P＜0.05或P＜0.01);RNAi组的T8(P＜0.05)、blank vector组和NS组的T8、T12-T14均低于sham组相应时点的阈值(P＜0.05或P＜0.01);RNAi组的T14高于sham组(P＜0.01);RNAi组的T12-T14分别高于blank vector组和NS组的相应时点的阈值(P＜0.05或P＜0.01);右后肢PWMT:不同时间点各组间比较,差异无统计学意义(P＞0.05)。
2.脊髓背角GFP表达:CCI后14d时,RNAi组脊髓背角神经细胞中GFP表达阳性,blank vector组无GFP的表达,与其余两组相同。
3.脊髓背角GFAP平均荧光强度:blank vector组和NS组最高,且两者比较无统计学意义(P＞0.05);RNAi组与sham组相似(P＞0.05),且均低于以上两组(P＜0.01)。
4.脊髓背角pCREB平均荧光强度:RNAi组CCI后14d时脊髓背角pCREB平均荧光强度明显弱于blank vector组和NS组(P＜0.01),但强于sham组(P＜0.05)。
5.脊髓背角Ast内pCREB平均荧光强度:RNAi组CCI后14d时脊髓背角Ast内pCREB平均荧光强度明显弱于blank vector组和NS组(P＜0.01),但与sham组无差异(P＞0.05)。
结论:1.连续鞘内注射pKCSHR-Puro/GFP-DREAM慢病毒可以明显改善CCI大鼠的痛行为。
2.DREAM基因下调可明显抑制外周神经伤害性刺激诱发的脊髓背角Ast的活化。
3.DREAM基因下调可显著抑制pCREB在脊髓背角的总体表达和Ast内的表达。
4.脊髓背角Ast的活性降低和脊髓背角pCREB的低表达可能在DREAM基因沉默治疗CCI大鼠疼痛中发挥重要作用。
Objective: To detect the application of DREAM silencing through siRNA mediated by lentiviral vector in gene therapy of rats neuropathic pain due to chronic constriction injury of the sciatic nerve (CCI), and to observe the changes of astrocyte activity and phosphorylation of cyclic AMP response element binding protein (pCREB) under the control of RNA interference(RNAi). And to find out the roles of astrocyte activity and pCREB in dorsal horn in gene therapy of neuropathic pain of rats suffered from CCI mediated by DREAM siRNA.
Method: To select 24 rats which were male and healthy, then to divide them randomly into 4 groups(n=6 each), that is, Group RNAi, Group blank vector, Group NS and Group sham. To measure the basic pain threshold before building the model(TO), including paw withdraw thermal latency(PWTL) and paw withdraw mechanical threshold(PWMT), then to repeat the operations once a day until 14th day(T14) after CCI. And we had continuously given pKCSHR-Puro/GFP- DREAM- LV (1×10~9 IU/ml) 5μl + NS 5μl or blank vector 5μl+ NS5μl or NS 10μl by intrathecal injection once a day from 8th day after CCI(T8) to 14th day(T14). At last, we took out the spinal cords(L4-5) and made them into paraffin sections, then through immunofluorescence method, we could observe the expressions of green fluorescent protein(GFP), glial fibrillary acidic protein (GFAP) and pCREB.
Result: Pain threshold: there were no differences among 4 groups with basic pain threshold(P>0.05); PWTL of left paw on T7-T10 and T12 in Group RNAi and T7-T10 in Group sham, and on T7-T14 in Group blank vector and NS were much lower than the respective basic pain threshold(P<0.05 or P<0.01); and those on T10、T11、T13 and T14 in Group RNAi were much higher than that on T7 in the group (P<0.01); And those on T9-T14 in blank vector and NS were much lower(P<0.05 or P<0.01 vs T7); PWTL of left paw on T13-T14 in Group blank vector and Group NS were lower than that in Group sham; and PWTL of left paw on T11,T13 and T14 in Group RNAi were higher than those in Group blank vector and NS (P<0.05). There were no differences among 4 groups with PWTL of right paw on all points(P>0.05). PWMT of left paw: all values noting post-CCI were lower than the level of preoperation. T8 in Group RNAi, T8 and T12-T14 in Group blank vector and Group NS were much lower than those on each point in Group sham(P<0.05 or P<0.01). T14 in Group RNAi was higher than the Group sham's(P<0.01). And T12-T14 in Group RNAi were also higher than that in Group blank vector and NS(P<0.05 or P<0.01). And the case with PWMT of right paw was the same as PWTL of right paw.
GFP: positive expression was only observed in dorsal horn in Group RNAi, and dark was in the views of other groups.
GFAP(average of fluorescence intensity): Group blank vector and Group NS were the highest. Also Group RNAi and Group sham were similar with each other(P>0.05), and both of which were lower than the groups above(P<0.01).
pCREB(average of fluorescence intensity) in dorsal horn: Group RNAi was significantly reduced(P<0.01 vs Group blank vector and NS), but higher than Group sham (P<0.05).
pCREB(average of fluorescence intensity) in astrocytes of dorsal horn: Group blank vector and Group NS were the highest. Also Group RNAi and Group sham were similar with each other(P>0.05), and both of which were lower than the groups above(P<0.01).
Conclusion: 1. The continuous-intrathecal injection of pKCSHR-Puro/GFP-DREAM-LV could evidently relieve pain of rats suffered from CCI in behavioristics.
2.The low expression of DREAM could inhibit the activation of astrocyte in dorsal horn due to nociceptive stimulus with sciatic nerve.
3.The low expression of DREAM could inhibit the total expression of pCREB in dorsal horn, especially in astrocyte.
4.The inhibition of astrocyte's activating and the expression of pCREB in dorsal horn may play an important part in gene therapy of rats with neuropathic pain through DREAM siRNA.
引文
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[1]严相默.临床疼痛学。第2版.延吉:延边人民出版社,1996,180-185.
[2]孙大金,杭燕南.实用临床麻醉学.北京:中国医药科技出版社,2001,1236-1253.
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[4]Min JJ,Gambhir SS.Gene therapy progress and prospects.Gene Ther,2004,11(2):115-125.
[5]Shiba H,Misawa T,Iida T,et al.Adenovirus vector-mediated gene therapy using iodized oil esters for hepatocellular carcinoma in rats.Anticancer Res.2008,28(1A):51-53.
[6]Ramirez PJ,Vickers SM,Ono HA,et al.Optimization of conditionally replicative adenovirus for pancreatic cancer and its evaluation in an orthotopic murine xenograft model.Am J Surg,2008,195(4):481-490.
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[9]Lebherz C, Maguire A, Tang W, et al. Novel AAV serotypes for improved ocular gene transfer. J Gene Med, 2008,10(4):375-382.
[10]Sinn PL, Goreham-Voss JD, Arias AC, et al. Enhanced gene expression conferred by stepwise modification of a nonprimate lentiviral vector. Hum Gene Ther, 2007,18(12): 1244-1252.
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[21]Jones KA, Peterlin BM. Control of RNA initiation and elongation at the HIV-1 promoter. Annu Rev Biochem, 1994,63: 717 - 743.
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[26]Naldini L, Blomer U, Gage F H, et al. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA, 1996, 93(21): 11382-11388.
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[28]Uchida N, Sutton RE, Friera AM, et al. HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0/G1 human hematopoietic stem cells. Proc Natl Acad Sci USA, 1998, 95(20): 11939-11944.
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