二苯乙烯苷对脑缺血再灌注大鼠大脑皮质NGF、PKAc及GAP-43蛋白表达的影响
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摘要
背景与目的脑缺血损伤后细胞的存活、增殖受多种信号途径的调节。研究显示,外源性神经生长因子(NGF)能够上调cAMP的表达,激活PKA通路,使轴突生长相关蛋白43(GAP-43)的表达增加,促进轴突再生,起到神经保护作用。近年来研究发现中药何首乌(polygonum multiflorum thunb)及其活性成分二苯乙烯苷(tetrahydroxystilbene glucoside,简称TSG)对脑缺血损伤具有保护作用,但其作用机制与量效关系仍不十分明确。另外,有研究显示二苯乙烯苷能够提高内源性神经生长因子的表达,从而提高小鼠的学习记忆能力,起到脑保护作用。本研究将在大鼠脑缺血-再灌注损伤模型上,以二苯乙烯苷(两组剂量)为干预手段,通过动态观察大鼠局灶性脑缺血再灌注后缺血半暗带NGF、PKAc与GAP-43蛋白的表达及小、大两组TSG剂量对三者的影响,结合病理、神经功能和细胞凋亡方面,探讨该药在脑缺血保护作用中的可能机制及量效关系,以期为脑缺血的防治以及新药的开发提供实验基础。
方法200～300g健康雄性SD大鼠,随机分为4组:对照组(n=24),模型组(n=24),小剂量TSG组(n=24),大剂量TSG组(n=24)。小剂量为60mg/kg/d、大剂量为120mg/kg/d两种剂量灌胃,给药体积5ml/kg/d,模型组以等量的生理盐水灌胃,第七天灌胃后1h行Longa线栓法制备大脑中动脉栓塞模型(MCAO)。按Longa的5级标准评分法评价神经功能缺损。再灌注6h、24h、48h、7d共4个时间点处死大鼠。分别采用HE染色观察缺血周边区病理组织学变化;原位末端脱氧核苷酸转移酶标记法(TUNEL)检测神经细胞凋亡;免疫组化法检测NGF、PKAc及GAP-43蛋白表达变化。
结果1、两种剂量TSG组神经功能缺损程度除6h时间点外其余各时间点均低于模型组。
2、模型组与两种剂量TSG组再灌注24h的HE染色均显示出典型的坏死灶和神经元丢失。
3、对照组检测到少量凋亡细胞;模型组与TSG组再灌注6h后凋亡细胞开始增多,24h达高峰,48h明显下降,7d仅有少量表达。与模型组对比,除7d外,其余各时间点两种剂量TSG组凋亡细胞数减少;两种剂量TSG组间无明显差异。
4、对照组各时间点检测到少量NGF、PKAc及GAP-43蛋白的表达。模型组与TSG组NGF、PKAc、GAP-43蛋白的表达变化基本一致,其中前两者再灌注6h后出现阳性表达,24h达到高峰,48h表达下降,7天少量表达;而GAP-43再灌注6h表达同对照组,24h表达增加,48h达高峰,7d仍有表达。对比模型组,TSG治疗组在各时间点NGF、PKAc及GAP-43蛋白的表达明显上调,两个TSG剂量组间无明显差异。
结论1.TSG能够诱导大鼠脑缺血-再灌注损伤后NGF蛋白表达上调,激活PKA通路,增加GAP-43蛋白的表达,促进轴突再生。
2.TSG两组剂量上调NGF、PKAc及GAP-43蛋白表达差异不明显。
Background and objective The cell survival and proliferation following ischemic brain damage was modulated by many signal transduction pathways. The expression of cAMP increased when treated with exogenous NGF,which activated the PKA pathyway and increased the expression of GAP-43 that made the neurite regenerate. Presently, it was reported that Chinese medicine polygonum multiflorum thunb and its active pharmaceutical ingredients tetrahydroxystilbene glucoside (TSG) had protective effects on cerebral ischemia,but the mechanism and Dose-effect relationship was not fully understood. Studies have shown the expression of NGF increased when treated with NGF in AD rats. In this study, we observed the protein expression of NGF、PKAc and GAP-43 and the effect of TSG. Furthermore, the impairment of brain tissue and apoptotic cells were detected to investigate the mechanism of neuroprotective and dose effect of TSG. The results may provide the experimental bases for the new drug development and therapeutic strategy on cerebral ischemia.
Methods The healthy male sprague-dawley rats weighting 200-300g were randomly divided into four groups: control group (n=24), I/R(ischemia/reperfusin)group (n=24), low dose (60mg/kg/d, n=24) and high dose(120mg/kg/d, n=24) TSG treatment group. After 6 days intragastric (ig) administration of TSG (treatment groups) or natural saline (I/R group). Transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Then, neurological behavior evaluation was performed by the method of Longa's scoring. The pathologic changes were observed by hematoxylin and eosin (HE) staining at 6 h, 12 h, 24 h and 7 d after reperfusion in cerebral cortex of rats. Meanwhile, apoptotic cells were detected by terminal deoxynucleotide transferase-mediated nick end labeling (TUNEL) technique. The protein expression of NGF、PKAc and GAP- 43 were measured with methods of immunohistochemistry.
Results
1. Compared with I/R group, treated with both dose of TSG could decrease the grade of the rat neurological defects except at 6 h after reperfusion.
2. Typical neural necrosis could be observed in I/R group and both TSG groups by HE staining at 24 h after reperfusion.
3. Few apoptotic cells were detected in control group. Apoptotic cells' numbers increased significantly at 6 h after reperfusion in I/R group and both TSG groups compared with in control group. The peak of apoptotic cells' numbers appeared at 24 h after reperfusion, and lasted to 48 h and 7 d after reperfusion. Treated with both doses of TSG could reduce apoptotic cells' numbers,compared with I/R group except at 7 d after reperfusion. There was no significant difference between low and high dose TSG treatment group.
4. The protein expression of NGF、PKAc and GAP-43 were detected few in control group. The protein expression of NGF and PKAc increased at 6h after cerebral reperfusion, reached maximum at 24h, reduced at 48h and maintained few at 7d in I/R group and both TSG groups. The protein expression of GAP-43 increased at 24h after cerebral reperfsion, reached maximum at 48h, and maintained positive at 7d in I/R group and both TSG groups. Compared with I/R group, treated with TSG could significantly increase the protein expression of NGF、PKAc and GAP-43 after reperfusion. There was no significant difference between low and high dose TSG treatment group.
Conclusions
1. The protein expression of NGF increased when treated with TSG after cerebral ischemia-reperfusion ,which activated the PKA pathyway and increased the protein expression of GAP-43 that made the neurite regenerate.
2. There was no significant difference between low and high dose TSG treatment group on the protein expression of NGF、PKAc and GAP-43.
方法200～300g健康雄性SD大鼠,随机分为4组:对照组(n=24),模型组(n=24),小剂量TSG组(n=24),大剂量TSG组(n=24)。小剂量为60mg/kg/d、大剂量为120mg/kg/d两种剂量灌胃,给药体积5ml/kg/d,模型组以等量的生理盐水灌胃,第七天灌胃后1h行Longa线栓法制备大脑中动脉栓塞模型(MCAO)。按Longa的5级标准评分法评价神经功能缺损。再灌注6h、24h、48h、7d共4个时间点处死大鼠。分别采用HE染色观察缺血周边区病理组织学变化;原位末端脱氧核苷酸转移酶标记法(TUNEL)检测神经细胞凋亡;免疫组化法检测NGF、PKAc及GAP-43蛋白表达变化。
结果1、两种剂量TSG组神经功能缺损程度除6h时间点外其余各时间点均低于模型组。
2、模型组与两种剂量TSG组再灌注24h的HE染色均显示出典型的坏死灶和神经元丢失。
3、对照组检测到少量凋亡细胞;模型组与TSG组再灌注6h后凋亡细胞开始增多,24h达高峰,48h明显下降,7d仅有少量表达。与模型组对比,除7d外,其余各时间点两种剂量TSG组凋亡细胞数减少;两种剂量TSG组间无明显差异。
4、对照组各时间点检测到少量NGF、PKAc及GAP-43蛋白的表达。模型组与TSG组NGF、PKAc、GAP-43蛋白的表达变化基本一致,其中前两者再灌注6h后出现阳性表达,24h达到高峰,48h表达下降,7天少量表达;而GAP-43再灌注6h表达同对照组,24h表达增加,48h达高峰,7d仍有表达。对比模型组,TSG治疗组在各时间点NGF、PKAc及GAP-43蛋白的表达明显上调,两个TSG剂量组间无明显差异。
结论1.TSG能够诱导大鼠脑缺血-再灌注损伤后NGF蛋白表达上调,激活PKA通路,增加GAP-43蛋白的表达,促进轴突再生。
2.TSG两组剂量上调NGF、PKAc及GAP-43蛋白表达差异不明显。
Background and objective The cell survival and proliferation following ischemic brain damage was modulated by many signal transduction pathways. The expression of cAMP increased when treated with exogenous NGF,which activated the PKA pathyway and increased the expression of GAP-43 that made the neurite regenerate. Presently, it was reported that Chinese medicine polygonum multiflorum thunb and its active pharmaceutical ingredients tetrahydroxystilbene glucoside (TSG) had protective effects on cerebral ischemia,but the mechanism and Dose-effect relationship was not fully understood. Studies have shown the expression of NGF increased when treated with NGF in AD rats. In this study, we observed the protein expression of NGF、PKAc and GAP-43 and the effect of TSG. Furthermore, the impairment of brain tissue and apoptotic cells were detected to investigate the mechanism of neuroprotective and dose effect of TSG. The results may provide the experimental bases for the new drug development and therapeutic strategy on cerebral ischemia.
Methods The healthy male sprague-dawley rats weighting 200-300g were randomly divided into four groups: control group (n=24), I/R(ischemia/reperfusin)group (n=24), low dose (60mg/kg/d, n=24) and high dose(120mg/kg/d, n=24) TSG treatment group. After 6 days intragastric (ig) administration of TSG (treatment groups) or natural saline (I/R group). Transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Then, neurological behavior evaluation was performed by the method of Longa's scoring. The pathologic changes were observed by hematoxylin and eosin (HE) staining at 6 h, 12 h, 24 h and 7 d after reperfusion in cerebral cortex of rats. Meanwhile, apoptotic cells were detected by terminal deoxynucleotide transferase-mediated nick end labeling (TUNEL) technique. The protein expression of NGF、PKAc and GAP- 43 were measured with methods of immunohistochemistry.
Results
1. Compared with I/R group, treated with both dose of TSG could decrease the grade of the rat neurological defects except at 6 h after reperfusion.
2. Typical neural necrosis could be observed in I/R group and both TSG groups by HE staining at 24 h after reperfusion.
3. Few apoptotic cells were detected in control group. Apoptotic cells' numbers increased significantly at 6 h after reperfusion in I/R group and both TSG groups compared with in control group. The peak of apoptotic cells' numbers appeared at 24 h after reperfusion, and lasted to 48 h and 7 d after reperfusion. Treated with both doses of TSG could reduce apoptotic cells' numbers,compared with I/R group except at 7 d after reperfusion. There was no significant difference between low and high dose TSG treatment group.
4. The protein expression of NGF、PKAc and GAP-43 were detected few in control group. The protein expression of NGF and PKAc increased at 6h after cerebral reperfusion, reached maximum at 24h, reduced at 48h and maintained few at 7d in I/R group and both TSG groups. The protein expression of GAP-43 increased at 24h after cerebral reperfsion, reached maximum at 48h, and maintained positive at 7d in I/R group and both TSG groups. Compared with I/R group, treated with TSG could significantly increase the protein expression of NGF、PKAc and GAP-43 after reperfusion. There was no significant difference between low and high dose TSG treatment group.
Conclusions
1. The protein expression of NGF increased when treated with TSG after cerebral ischemia-reperfusion ,which activated the PKA pathyway and increased the protein expression of GAP-43 that made the neurite regenerate.
2. There was no significant difference between low and high dose TSG treatment group on the protein expression of NGF、PKAc and GAP-43.
引文
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