NF-κB信号通路中炎症因子在慢性致痫大鼠海马的表达及PDTC干预的研究
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摘要
目的:研究戊四氮(Pentylenetetrazole,PTZ)慢性致痫大鼠及应用NF-κB信号传导通路抑制剂吡咯烷二硫代氨基甲酸盐(pyrrolidine dithiocarbarnate,PDTC)干预后对大鼠行为学的影响以及在海马组织内NF-κB/P65、炎症因子TNF-α、IL-1β及抗炎因子IL-10 mRNA的表达变化,探讨NF-κB/P65、TNF-α、IL-1β及IL-10在慢性癫痫中的作用及PDTC的抗痫机制。
方法:将SD大鼠随机分为生理盐水对照组、PTZ致痫组(模型组)、和PDTC干预组共3组。模型组大鼠用亚惊厥剂量的PTZ(35mg/kg)行腹腔注射,制备慢性癫痫模型;干预组于注射PTZ 60min前行腹腔注射PDTC(100mg/kg);对照组以等量生理盐水代替PTZ行腹腔注射。每只大鼠每日给药1次,至处死当天,共持续35d。各组存活的大鼠分别于给药后14d、21d、28d和35d四个时间点处死。每天观察给药后60min大鼠的行为学变化,采用Racine行为学评分评价致痫大鼠痫性发作程度;应用逆转录聚合酶链式反应(Reverse transcription polymerase chain reaction,RT-PCR)检测大鼠海马组织中NF-κB/P65、TNF-α、IL-1β、IL-10 mRNA的表达。
结果:(1)大鼠行为学观察:对照组未观察到癫痫发作表现;模型组在给药14d时有27.2%的大鼠开始出现Ⅰ-Ⅱ级癫痫发作,严重时期出现在21d～28d,造模成功率:78.8%;干预组于给药14d时6.1%的大鼠开始出现Ⅰ-Ⅱ级癫痫发作,严重时期出现在24d～28d,与相应时期模型组相比发作程度明显减轻,Racine评分明显下降(p<0.01),造模成功率下降(p<0.05)。(2)经直线相关性分析,模型组和干预组NF-κB/P65、TNF-α、IL-1βmRNA及模型组IL-10 mRNA的表达量在四个时间点上均与Racine评分呈正相关关系。(3)NF-κB/P65、TNF-α、IL-1β、IL-10 mRNA的表达:在四个时间点上,对照组无明显变化,模型组则均明显高于对照组和干预组(p<0.01),表达量在28d达高峰;干预组NF-κB/P65、TNF-α、IL-1βmRNA的表达在21d和28d两个时间点明显高于对照组(p<0.01),35d时有所下降,但仍高于对照组(p<0.05),14d时与对照组比较无明显变化(p>0.05)。干预组IL-10 mRNA的表达在四个时间点与对照组相比均无明显变化(p>0.05)。
结论:腹腔注射亚惊厥剂量的PTZ (35mg/kg)可诱导大鼠出现慢性癫痫发作,同时海马内NF-κB/P65、TNF-α、IL-1β及IL-10 mRNA的表达水平明显增高; PDTC干预后大鼠癫痫发作程度下降,同时海马内NF-κB/P65、TNF-α、IL-1β及IL-10 mRNA的表达水平下调,提示PDTC具有一定的抗癫痫作用,其机制可能与下调海马内NF-κB/P65、TNF-α、IL-1β及IL-10的表达水平有关。
Objective: To investigate the effect of PDTC on the changes of behavior, NF-κB/P65, TNF-α, IL-1βand IL-10 in hippocampus of PTZ induced epileptic rats and the possible antiepileptic mechanism of PDTC.
Methods:The adult SD rats were randomly divided into three groups:normal saline control group (Control group),PTZ-induced epilepsy group(Model group) and PDTC intervention group (Intervention group). Chronic epilepsy model was produced by intraperitoneally injection of PTZ (35mg/kg); rats in intervention group were intraperitoneally injected with 100mg/kg of PDTC at 60min before injection of PTZ, while the rats in control group were injected with the same volume of saline by intraperitoneally. The saline / PTZ / PDTC were injected daily according to above protocol , until the rat was executed,up to 35 days. Day 14 ,21 ,28 , 35 were selected individually as four observation points. The behavioral changes of the rats were observed and assessed the degree of seizure by Racine score daily 60min after the injection. The hippocampuses were taken out , and mRNAs of NF-κB/P65, TNF-α, IL-1βand IL-10 were measured by RT-PCR .
Results: (1) Observation of the praxiology: there were no rats showed epileptic symptom in contrl group. 27.2 percent of the rats in model group showed gradeⅠ-Ⅱof epilepsy at day 14, the serious time was among 21th to 28th day, modeling success rate: 78.8 percent. While there were 6.1 percent of the rats showed epileptic symptom in intervention group at day 14, the serious time was among 24th to 28th day, the degree of epilepsy and the Racine score were more lower than that in model group (p<0.01),and the modeling success rate of epileptic rats was more lower than that in model group (p<0.05).(2)according to the linear correlation analysis,the expression of NF-κB/P65, TNF-α, IL-1βmRNA in model and intervention groups and IL-10 mRNA in intervention group at four observation points was positively correlated with the Racine score. (3) the expression of NF-κB/P65, TNF-α, IL-1β、IL-10 mRNA was no change in control group at four observation points;the expression in model group was significantly higher than that of the intervention and control group at four observation points (p<0.01), and peaked at day 28.while the expression in intervention group of NF-κB/P65, TNF-α, IL-1βmRNA in hippocampus was higher than that of the control group at day 21、28 (p<0.01) and at day 35 (p<0.05),there was no change at day 14 (p>0.05), and peaked at day 28.In intervention group, the expression of IL-10 mRNA is as same as that in the control group (P>0.05) at four observation points .
Conclusion: Epilepsy can be succesfully induced in rat by intraperitoneally injection of sub-eclampsia dose of PTZ(35mg/kg), meanwhile, the expression of NF-κB/P65, TNF-α, IL-1βand IL-10 mRNA increased obviously in hippocampus ; after intervention with PDTC , the epileptic symptom in rat was relieve , at the same time the expressions of NF-κB/P65, TNF-α, IL-1βand IL-10 mRNA were decreased significantly, suggesting that PDTC has a certain antiepileptic effect, its mechanism may be reduced the expression levels of NF-κB/P65, TNF-α, IL-1βand IL-10 in the hippocampus.
方法:将SD大鼠随机分为生理盐水对照组、PTZ致痫组(模型组)、和PDTC干预组共3组。模型组大鼠用亚惊厥剂量的PTZ(35mg/kg)行腹腔注射,制备慢性癫痫模型;干预组于注射PTZ 60min前行腹腔注射PDTC(100mg/kg);对照组以等量生理盐水代替PTZ行腹腔注射。每只大鼠每日给药1次,至处死当天,共持续35d。各组存活的大鼠分别于给药后14d、21d、28d和35d四个时间点处死。每天观察给药后60min大鼠的行为学变化,采用Racine行为学评分评价致痫大鼠痫性发作程度;应用逆转录聚合酶链式反应(Reverse transcription polymerase chain reaction,RT-PCR)检测大鼠海马组织中NF-κB/P65、TNF-α、IL-1β、IL-10 mRNA的表达。
结果:(1)大鼠行为学观察:对照组未观察到癫痫发作表现;模型组在给药14d时有27.2%的大鼠开始出现Ⅰ-Ⅱ级癫痫发作,严重时期出现在21d～28d,造模成功率:78.8%;干预组于给药14d时6.1%的大鼠开始出现Ⅰ-Ⅱ级癫痫发作,严重时期出现在24d～28d,与相应时期模型组相比发作程度明显减轻,Racine评分明显下降(p<0.01),造模成功率下降(p<0.05)。(2)经直线相关性分析,模型组和干预组NF-κB/P65、TNF-α、IL-1βmRNA及模型组IL-10 mRNA的表达量在四个时间点上均与Racine评分呈正相关关系。(3)NF-κB/P65、TNF-α、IL-1β、IL-10 mRNA的表达:在四个时间点上,对照组无明显变化,模型组则均明显高于对照组和干预组(p<0.01),表达量在28d达高峰;干预组NF-κB/P65、TNF-α、IL-1βmRNA的表达在21d和28d两个时间点明显高于对照组(p<0.01),35d时有所下降,但仍高于对照组(p<0.05),14d时与对照组比较无明显变化(p>0.05)。干预组IL-10 mRNA的表达在四个时间点与对照组相比均无明显变化(p>0.05)。
结论:腹腔注射亚惊厥剂量的PTZ (35mg/kg)可诱导大鼠出现慢性癫痫发作,同时海马内NF-κB/P65、TNF-α、IL-1β及IL-10 mRNA的表达水平明显增高; PDTC干预后大鼠癫痫发作程度下降,同时海马内NF-κB/P65、TNF-α、IL-1β及IL-10 mRNA的表达水平下调,提示PDTC具有一定的抗癫痫作用,其机制可能与下调海马内NF-κB/P65、TNF-α、IL-1β及IL-10的表达水平有关。
Objective: To investigate the effect of PDTC on the changes of behavior, NF-κB/P65, TNF-α, IL-1βand IL-10 in hippocampus of PTZ induced epileptic rats and the possible antiepileptic mechanism of PDTC.
Methods:The adult SD rats were randomly divided into three groups:normal saline control group (Control group),PTZ-induced epilepsy group(Model group) and PDTC intervention group (Intervention group). Chronic epilepsy model was produced by intraperitoneally injection of PTZ (35mg/kg); rats in intervention group were intraperitoneally injected with 100mg/kg of PDTC at 60min before injection of PTZ, while the rats in control group were injected with the same volume of saline by intraperitoneally. The saline / PTZ / PDTC were injected daily according to above protocol , until the rat was executed,up to 35 days. Day 14 ,21 ,28 , 35 were selected individually as four observation points. The behavioral changes of the rats were observed and assessed the degree of seizure by Racine score daily 60min after the injection. The hippocampuses were taken out , and mRNAs of NF-κB/P65, TNF-α, IL-1βand IL-10 were measured by RT-PCR .
Results: (1) Observation of the praxiology: there were no rats showed epileptic symptom in contrl group. 27.2 percent of the rats in model group showed gradeⅠ-Ⅱof epilepsy at day 14, the serious time was among 21th to 28th day, modeling success rate: 78.8 percent. While there were 6.1 percent of the rats showed epileptic symptom in intervention group at day 14, the serious time was among 24th to 28th day, the degree of epilepsy and the Racine score were more lower than that in model group (p<0.01),and the modeling success rate of epileptic rats was more lower than that in model group (p<0.05).(2)according to the linear correlation analysis,the expression of NF-κB/P65, TNF-α, IL-1βmRNA in model and intervention groups and IL-10 mRNA in intervention group at four observation points was positively correlated with the Racine score. (3) the expression of NF-κB/P65, TNF-α, IL-1β、IL-10 mRNA was no change in control group at four observation points;the expression in model group was significantly higher than that of the intervention and control group at four observation points (p<0.01), and peaked at day 28.while the expression in intervention group of NF-κB/P65, TNF-α, IL-1βmRNA in hippocampus was higher than that of the control group at day 21、28 (p<0.01) and at day 35 (p<0.05),there was no change at day 14 (p>0.05), and peaked at day 28.In intervention group, the expression of IL-10 mRNA is as same as that in the control group (P>0.05) at four observation points .
Conclusion: Epilepsy can be succesfully induced in rat by intraperitoneally injection of sub-eclampsia dose of PTZ(35mg/kg), meanwhile, the expression of NF-κB/P65, TNF-α, IL-1βand IL-10 mRNA increased obviously in hippocampus ; after intervention with PDTC , the epileptic symptom in rat was relieve , at the same time the expressions of NF-κB/P65, TNF-α, IL-1βand IL-10 mRNA were decreased significantly, suggesting that PDTC has a certain antiepileptic effect, its mechanism may be reduced the expression levels of NF-κB/P65, TNF-α, IL-1βand IL-10 in the hippocampus.
引文
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