椒苯酮胺对大鼠脑缺血再灌注损伤的保护作用及机制研究
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摘要
目的：
脑血管疾病是世界三大致死性疾病之一,具有高发病率、高致残率、高死亡率、高复发率的特点。脑血管病是指在脑血管壁病变或血流障碍基础上发生的局限性或弥漫性脑功能障碍,65岁以上的中老年人多发,是中老年人致死和致残的主要疾病,严重危害人类的健康和生活质量。缺血性脑缺血疾病占脑血管疾病的70-80%。截止目前,脑缺血损伤的病理生理机制尚未完全明确,大量研究认为其发病机制可能与能量代谢障碍、兴奋性氨基酸毒性作用、一氧化氮的大量合成、氧自由基损伤、脂质过氧化反应、细胞内Ca2+超载、炎症反应、细胞凋亡等机制相关。目前,临床上对缺血性脑血管疾病治疗主要有溶栓治疗和神经保护治疗两大类。一方面,溶栓治疗虽然取得明确的临床治疗效果,但是受到治疗时间窗,颅内出血、脑水肿等并发症,以及再闭塞率等方面的限制。另一方面,神经保护药物治疗虽然具有广阔的前景,但是大多数药物虽然在动物实验中具有效果,但是进入临床效果亦不甚理想或者存在严重的不良反应,因此目前仍然缺乏理性的神经保护药物。本课题在以往研究的基础上,研究钙离子增敏剂椒苯酮胺对大鼠脑缺血再灌注损伤是否具有神经保护作用,以及进一步探讨其可能的作用机制,为该化合物进一步发展为具有自主知识产权的,治疗缺血性脑血管病的创新药物寻找理论基础。
方法：
第一部分,实验大鼠随机分为假手术组、模型组、PPTA低、中、高剂量组(2.5mg/kg、5mg/kg、10mg/kg)和阳性对照依达拉奉组(6mg/kg)。首先,采用经典的栓线法致大鼠大脑中动脉阻塞(MCAO)方法造成局灶性脑缺血再灌注损伤模型,脑缺血1h后静脉注射给药。模型动物缺血2h再灌注24h后,进行Zea-longa 5分制神经功能学评分方法,以评估动物神经损伤程度；测定实验大鼠脑组织含水量,以评估其脑水肿的程度；用2,3,5-氯化三苯基四氮唑(TTC)染色法测定梗死体积百分比。其次,使用Pulsinelli法建立全脑缺血20min再灌注模型,采用提前给药7d,运用Morris水迷宫,进行定向航行实验和空间探索实验,检测PPTA对全脑缺血再灌注大鼠模型空间认知能力的影响。
第二部分,采用栓线法致大鼠大脑中动脉阻塞(MCAO)方法造成局灶性脑缺血再灌注损伤模型。实验动物缺血2h再灌注24h后,采用黄嘌呤氧化法检测SOD活力,用硫代巴比妥酸显色法测定脑组织MDA含量,用硝酸还原法测定脑组织中NO含量,用NOS检测试剂盒测定脑组织提取液NOS活性,用考马斯亮蓝法组织蛋白含量测定,从而综合反映缺血再灌注时,实验动物脑组织中脂质过氧化反应以及氧自由基损伤的程度,从而研究PPTA是否具有对抗脂质过氧化反应和氧自由基损伤的作用。
第三部分,采用栓线法致大鼠大脑中动脉阻塞(MCAO)方法造成局灶性脑缺血再灌注损伤模型。缺血2h再灌注24h后,采用real-time PCR检测动物脑组织中炎症反应因子(IL-1β、TNF-a),及细胞凋亡因子(caspase-3、Hsp70)的表达,检测缺血再灌注时,动物脑组织中炎症反应以及细胞凋亡的变化程度,研究PPTA是否具有抑制炎症反应和抗细胞凋亡的作用。
结果：
缺血2h再灌注24h后,假手术组大鼠表现正常,评分为0分。与假手术组相比,模型组大鼠神经功能评分显著升高,其脑组织含水量和梗死体积较假手术组也有显著增加；全脑缺血20min后,运用Morris水迷宫进行定向航行实验和空间探索实验中,模型组大鼠潜伏期增加,空间认知能力下降,提示大鼠脑缺血后神经功能严重损伤；MCAO模型组大鼠较假手术组脑组织中SOD活力和GSH含量降低,NOS活力、MDA和NO含量显著增高,提示其神经细胞在脑缺血再灌注时受到氧自由基和脂质过氧化损伤；同时脑组织中IL-1β、TNF-a、Caspase-3、Hsp70等因子表达升高,验证了炎症反应和细胞凋亡也参与了缺血再灌注损伤病理损伤过程。
第一部分,PPTA中剂量组和高剂量组可显著降低行为评分,与模型组比较有显著性差异(P=0.027,P=0.017)；中剂量组和高剂量组脑组织含水量显著低于模型组(P＝0.001,P=0.001);PPTA中、高剂量组均可显著缩小缺血侧脑组织梗塞体积,与模型组相比有非常显著差异(P＝0.035,P＝0.003)。Morris水迷宫实验中PPTA低、中、高剂量组,定向航行实验中的潜伏期第4天,模型组的定向航行实验潜伏期显著高于假手术组(P<0.05)；第5天,PPTA低、中、高剂量组潜伏期显著低于模型组(P<0.01)。第6天,空间探索实验表明,PPTA低、中、高剂量组第一次到达平台所在位置的时间均显著低于模型组(P<0.01)；与模型组相比,PPTA低、中、高剂量组可显著增加实验动物留在目的象限的探索时间和探索路程(P<0.05,P<0.01,P<0.01)；不同时间点的各组两两比较发现,各组大鼠的游泳速度没有明显差异,提示PPTA具有神经保护作用。
第二部分：与模型组比较,PPTA高剂量组(10mg/kg),大脑SOD活力显著高于模型组(P=0.041);PPTA低、中、高剂量(2.5 mg/kg、5 mg/kg、10 mg/kg)脑组织MDA含量显著低于模型组(P=0.000,P=0.000,P=0.000)；高剂量组(10mg/kg)大脑GSH含量显著高于模型组(P=0.007)；脑组织NOS活力均显著低于模型组(P=0.030,P=0.006,P=0.004)；NO含量显著降低(P=0.000,P=0.000,P=0.000),提示PPTA可能通过提高抗氧化酶活性,清除氧自由基,抑制脂质过氧化反应,抑制NOS活性,减少NO的生成,抑制NO介导的毒性作用,发挥神经保护作用。
第三部分：与模型组比较,PPTA低、中剂量的IL-1βmRNA表达无显著性差异(P=0.254,P=0.099),PPTA高剂量组较模型组显著降低IL-1βmRNA的表达(P=0.001); PPTA高剂量较模型组亦可显著降低TNF-a mRNA的表达(P =0.018); PPTA中、高剂量组(5mg/kg、10mg/kg)则显著降低Caspase-3 mRNA的表达(P=0.007, P=0.001); PPTA低剂量、中、高剂量组(2.5mg/kg、5mg/kg、10mg/kg)与模型组比较显著降低HSP70表达(P=0.046,P=0.038,P=0.027),提示PPTA可能通过抗炎、抗细胞凋亡等机制,发挥神经保护作用。
结论：
1. PPTA具有神经保护作用；
2. PPTA可能通过对抗氧自由基损伤和脂质过氧化反应,实现神经保护作用；
3. PPTA可能通过抑制炎症反应和细胞凋亡,实现神经保护作用。
Objective: Cerebrovascular diseases have the characteristics of high morbility, high rate of mutilation and high mortality; therefore they can do great harm to human health. The patho-physiological mechanisms of cerebrovascular diseases haven't been fully made out till now. Ideal drugs for successful prevention and treatment cerebrovascular diseases still lack according to recent reports. Based on previous study, present study was performed to test the neuroprotective effect of piperphentonamine hydrochloride (PPTA) and investigate the potential underlying mechanisms in focal cerebral ischemia-reperfusion in rats. And this study may have an important implication in piperphentonamine hydrochloride growing to a new creative drug which has independence intellectual property rights for future treatment of patients suffered with cerebrovascular diseases.
Methods:There are four parts of the study.
1. Sprague-Dawley rats were randomly divided into the sham group, the ischemia-reperfusion group, the PPTA treated group (2.5,5,10 mg·kg-1) and the edaravone treated group (6 mg·kg-1). Rats were subjected to 24h of reperfusion following ischemia for 2h induced by middle cerebral artery occlusion (MCAO). The different doses of PPTA were intravenously administered to rats after 1h of the onset of ischemia. The neurological behavioral test was performed 24h after reperfusion by using the Zea-longa scores. Infarction volumes with TTC-staining and moisture content were calculated. Using global brain ischemia produced by the four vessels occluding method (Pulsinelli,1986), the MORRIS water maze test had been carried out in rats.
2. Sprague-Dawley rats were randomly divided into group as some as Part1. Rats were subjected to 24h of reperfusion following ischemia for 2h induced by middle cerebral artery occlusion (MCAO). The different doses of PPTA were intravenously administered to rats after 1h of the onset of ischemia. The changes of water content, the activity of SOD, GSH, NOS and the content of MDA and NO in brain tissue were measured.
3.Middle cerebral artery occlusion(MCAO)was employed to establish focal cerebral ischemia-reperfusion model in rats, then IL-1β, TNF-a, Caspase-3 and hsp-70 mRNA expression were measured by Real Time-PCR.
Result:
1. Focal cerebral ischemia-reperfusion, induced by MCAO, PPTA administration groups(5mg/kg、10 mg/kg) improved neurological deterioration score, compared with model group. PPTA administration indicated by a significant decrease in the infarction volume and brain tissue water content in rats after focal ischemia and reperfusion (P<0.01). PPTA displayed escape latency improvement as indicated by a significant increase in the swimming distance and duration in the target quadrant after global brain ischemia and reperfusion.
2. Compared with model group, in addition, less oxidative damage was detected in the PPTA-treated brain of rats, especially with the dose of 10 mg/kg, including the reduction of MDA levels and NOS activity, the increased activity of SOD and GSH which are antioxidant enzymes especially with the dose of 10 mg/kg, including the reduction of MDA levels and NOS activity, the increased activity of SOD and GSH which are antioxidant enzymes.
3. Compared with the model group, the expression levels of TNF-a, IL-1β, Caspase-3, HSP70 mRNA in PPTA treated group were distinctively lower.
Conclusion:
1. Piperphentonamine hydrochloride (PPTA) have the neuroprotective effect
2. The neuroprotective effects of PPTA were greatly associated with inhibition of lipid peroxidation reaction and scavenging free radical.
3. The neuroprotective effects of PPTA may performan with inhibiting apoptosis and inflammatory reaction.
脑血管疾病是世界三大致死性疾病之一,具有高发病率、高致残率、高死亡率、高复发率的特点。脑血管病是指在脑血管壁病变或血流障碍基础上发生的局限性或弥漫性脑功能障碍,65岁以上的中老年人多发,是中老年人致死和致残的主要疾病,严重危害人类的健康和生活质量。缺血性脑缺血疾病占脑血管疾病的70-80%。截止目前,脑缺血损伤的病理生理机制尚未完全明确,大量研究认为其发病机制可能与能量代谢障碍、兴奋性氨基酸毒性作用、一氧化氮的大量合成、氧自由基损伤、脂质过氧化反应、细胞内Ca2+超载、炎症反应、细胞凋亡等机制相关。目前,临床上对缺血性脑血管疾病治疗主要有溶栓治疗和神经保护治疗两大类。一方面,溶栓治疗虽然取得明确的临床治疗效果,但是受到治疗时间窗,颅内出血、脑水肿等并发症,以及再闭塞率等方面的限制。另一方面,神经保护药物治疗虽然具有广阔的前景,但是大多数药物虽然在动物实验中具有效果,但是进入临床效果亦不甚理想或者存在严重的不良反应,因此目前仍然缺乏理性的神经保护药物。本课题在以往研究的基础上,研究钙离子增敏剂椒苯酮胺对大鼠脑缺血再灌注损伤是否具有神经保护作用,以及进一步探讨其可能的作用机制,为该化合物进一步发展为具有自主知识产权的,治疗缺血性脑血管病的创新药物寻找理论基础。
方法：
第一部分,实验大鼠随机分为假手术组、模型组、PPTA低、中、高剂量组(2.5mg/kg、5mg/kg、10mg/kg)和阳性对照依达拉奉组(6mg/kg)。首先,采用经典的栓线法致大鼠大脑中动脉阻塞(MCAO)方法造成局灶性脑缺血再灌注损伤模型,脑缺血1h后静脉注射给药。模型动物缺血2h再灌注24h后,进行Zea-longa 5分制神经功能学评分方法,以评估动物神经损伤程度；测定实验大鼠脑组织含水量,以评估其脑水肿的程度；用2,3,5-氯化三苯基四氮唑(TTC)染色法测定梗死体积百分比。其次,使用Pulsinelli法建立全脑缺血20min再灌注模型,采用提前给药7d,运用Morris水迷宫,进行定向航行实验和空间探索实验,检测PPTA对全脑缺血再灌注大鼠模型空间认知能力的影响。
第二部分,采用栓线法致大鼠大脑中动脉阻塞(MCAO)方法造成局灶性脑缺血再灌注损伤模型。实验动物缺血2h再灌注24h后,采用黄嘌呤氧化法检测SOD活力,用硫代巴比妥酸显色法测定脑组织MDA含量,用硝酸还原法测定脑组织中NO含量,用NOS检测试剂盒测定脑组织提取液NOS活性,用考马斯亮蓝法组织蛋白含量测定,从而综合反映缺血再灌注时,实验动物脑组织中脂质过氧化反应以及氧自由基损伤的程度,从而研究PPTA是否具有对抗脂质过氧化反应和氧自由基损伤的作用。
第三部分,采用栓线法致大鼠大脑中动脉阻塞(MCAO)方法造成局灶性脑缺血再灌注损伤模型。缺血2h再灌注24h后,采用real-time PCR检测动物脑组织中炎症反应因子(IL-1β、TNF-a),及细胞凋亡因子(caspase-3、Hsp70)的表达,检测缺血再灌注时,动物脑组织中炎症反应以及细胞凋亡的变化程度,研究PPTA是否具有抑制炎症反应和抗细胞凋亡的作用。
结果：
缺血2h再灌注24h后,假手术组大鼠表现正常,评分为0分。与假手术组相比,模型组大鼠神经功能评分显著升高,其脑组织含水量和梗死体积较假手术组也有显著增加；全脑缺血20min后,运用Morris水迷宫进行定向航行实验和空间探索实验中,模型组大鼠潜伏期增加,空间认知能力下降,提示大鼠脑缺血后神经功能严重损伤；MCAO模型组大鼠较假手术组脑组织中SOD活力和GSH含量降低,NOS活力、MDA和NO含量显著增高,提示其神经细胞在脑缺血再灌注时受到氧自由基和脂质过氧化损伤；同时脑组织中IL-1β、TNF-a、Caspase-3、Hsp70等因子表达升高,验证了炎症反应和细胞凋亡也参与了缺血再灌注损伤病理损伤过程。
第一部分,PPTA中剂量组和高剂量组可显著降低行为评分,与模型组比较有显著性差异(P=0.027,P=0.017)；中剂量组和高剂量组脑组织含水量显著低于模型组(P＝0.001,P=0.001);PPTA中、高剂量组均可显著缩小缺血侧脑组织梗塞体积,与模型组相比有非常显著差异(P＝0.035,P＝0.003)。Morris水迷宫实验中PPTA低、中、高剂量组,定向航行实验中的潜伏期第4天,模型组的定向航行实验潜伏期显著高于假手术组(P<0.05)；第5天,PPTA低、中、高剂量组潜伏期显著低于模型组(P<0.01)。第6天,空间探索实验表明,PPTA低、中、高剂量组第一次到达平台所在位置的时间均显著低于模型组(P<0.01)；与模型组相比,PPTA低、中、高剂量组可显著增加实验动物留在目的象限的探索时间和探索路程(P<0.05,P<0.01,P<0.01)；不同时间点的各组两两比较发现,各组大鼠的游泳速度没有明显差异,提示PPTA具有神经保护作用。
第二部分：与模型组比较,PPTA高剂量组(10mg/kg),大脑SOD活力显著高于模型组(P=0.041);PPTA低、中、高剂量(2.5 mg/kg、5 mg/kg、10 mg/kg)脑组织MDA含量显著低于模型组(P=0.000,P=0.000,P=0.000)；高剂量组(10mg/kg)大脑GSH含量显著高于模型组(P=0.007)；脑组织NOS活力均显著低于模型组(P=0.030,P=0.006,P=0.004)；NO含量显著降低(P=0.000,P=0.000,P=0.000),提示PPTA可能通过提高抗氧化酶活性,清除氧自由基,抑制脂质过氧化反应,抑制NOS活性,减少NO的生成,抑制NO介导的毒性作用,发挥神经保护作用。
第三部分：与模型组比较,PPTA低、中剂量的IL-1βmRNA表达无显著性差异(P=0.254,P=0.099),PPTA高剂量组较模型组显著降低IL-1βmRNA的表达(P=0.001); PPTA高剂量较模型组亦可显著降低TNF-a mRNA的表达(P =0.018); PPTA中、高剂量组(5mg/kg、10mg/kg)则显著降低Caspase-3 mRNA的表达(P=0.007, P=0.001); PPTA低剂量、中、高剂量组(2.5mg/kg、5mg/kg、10mg/kg)与模型组比较显著降低HSP70表达(P=0.046,P=0.038,P=0.027),提示PPTA可能通过抗炎、抗细胞凋亡等机制,发挥神经保护作用。
结论：
1. PPTA具有神经保护作用；
2. PPTA可能通过对抗氧自由基损伤和脂质过氧化反应,实现神经保护作用；
3. PPTA可能通过抑制炎症反应和细胞凋亡,实现神经保护作用。
Objective: Cerebrovascular diseases have the characteristics of high morbility, high rate of mutilation and high mortality; therefore they can do great harm to human health. The patho-physiological mechanisms of cerebrovascular diseases haven't been fully made out till now. Ideal drugs for successful prevention and treatment cerebrovascular diseases still lack according to recent reports. Based on previous study, present study was performed to test the neuroprotective effect of piperphentonamine hydrochloride (PPTA) and investigate the potential underlying mechanisms in focal cerebral ischemia-reperfusion in rats. And this study may have an important implication in piperphentonamine hydrochloride growing to a new creative drug which has independence intellectual property rights for future treatment of patients suffered with cerebrovascular diseases.
Methods:There are four parts of the study.
1. Sprague-Dawley rats were randomly divided into the sham group, the ischemia-reperfusion group, the PPTA treated group (2.5,5,10 mg·kg-1) and the edaravone treated group (6 mg·kg-1). Rats were subjected to 24h of reperfusion following ischemia for 2h induced by middle cerebral artery occlusion (MCAO). The different doses of PPTA were intravenously administered to rats after 1h of the onset of ischemia. The neurological behavioral test was performed 24h after reperfusion by using the Zea-longa scores. Infarction volumes with TTC-staining and moisture content were calculated. Using global brain ischemia produced by the four vessels occluding method (Pulsinelli,1986), the MORRIS water maze test had been carried out in rats.
2. Sprague-Dawley rats were randomly divided into group as some as Part1. Rats were subjected to 24h of reperfusion following ischemia for 2h induced by middle cerebral artery occlusion (MCAO). The different doses of PPTA were intravenously administered to rats after 1h of the onset of ischemia. The changes of water content, the activity of SOD, GSH, NOS and the content of MDA and NO in brain tissue were measured.
3.Middle cerebral artery occlusion(MCAO)was employed to establish focal cerebral ischemia-reperfusion model in rats, then IL-1β, TNF-a, Caspase-3 and hsp-70 mRNA expression were measured by Real Time-PCR.
Result:
1. Focal cerebral ischemia-reperfusion, induced by MCAO, PPTA administration groups(5mg/kg、10 mg/kg) improved neurological deterioration score, compared with model group. PPTA administration indicated by a significant decrease in the infarction volume and brain tissue water content in rats after focal ischemia and reperfusion (P<0.01). PPTA displayed escape latency improvement as indicated by a significant increase in the swimming distance and duration in the target quadrant after global brain ischemia and reperfusion.
2. Compared with model group, in addition, less oxidative damage was detected in the PPTA-treated brain of rats, especially with the dose of 10 mg/kg, including the reduction of MDA levels and NOS activity, the increased activity of SOD and GSH which are antioxidant enzymes especially with the dose of 10 mg/kg, including the reduction of MDA levels and NOS activity, the increased activity of SOD and GSH which are antioxidant enzymes.
3. Compared with the model group, the expression levels of TNF-a, IL-1β, Caspase-3, HSP70 mRNA in PPTA treated group were distinctively lower.
Conclusion:
1. Piperphentonamine hydrochloride (PPTA) have the neuroprotective effect
2. The neuroprotective effects of PPTA were greatly associated with inhibition of lipid peroxidation reaction and scavenging free radical.
3. The neuroprotective effects of PPTA may performan with inhibiting apoptosis and inflammatory reaction.
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