超早期针刺对急性脑缺血大鼠能量代谢的影响及其机制研究
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摘要
目的：
脑血管病已成为危害我国中老年人身体健康和生命的主要疾病,急性缺血性脑血管疾病占脑血管疾病的43%-65%,病死率为15%-25%,其高发病率,高死亡率和高致残率给国家及患者带来了沉重的经济和社会负担。临床中许多缺血性脑血管病发病后超早期急救不及时,脑细胞在短期缺血、缺氧后形成了不可逆的损伤,最终造成死亡或恢复期遗留严重后遗症。在发病后最短时间内,使用安全有效、简便易行的急救措施对脑组织进行有效的保护,将对患者的预后产生积极影响。药物疗法仍是目前治疗缺血性脑血管病的有效手段之一,但药物疗法均有一定的毒、副作用,而针刺疗法已广泛应用脑血管病恢复期治疗,并且已被越来越普遍地应用于缺血性中风急性期治疗,在缺血后立即给予针刺治疗则能使局部脑血流显著增加,使缺血组织局部维持有效的血供,对抗缺血引起的损伤；缺血后再灌注期针刺增加局部脑血供,使脑梗死面积显著减小,神经功能得到有效的保护。因此,针刺超早期介入的意义值得重视。本研究在前期采用microPET观察到超早期针刺对脑缺血葡萄糖代谢改善的基础上,进一步探讨超早期针刺抗脑缺血损伤的作用机理,为临床针刺治疗缺血性中风提供一定的实验依据。
方法：
SPF级雌性SD大鼠140只,3月龄,体重200～250g,随机分为7组,正常组、穴位2h组、非穴位2h组、模型2h组、穴位24h组、非穴位24h组、模型24h组,每组各20只,其中10只用来灌注取脑,10只取新鲜脑组织。采用开颅法电凝大脑中动脉造模,制作右侧大鼠大脑中动脉急性脑缺血模型。穴位组取“百会”、“水沟”针刺,以120次／分左右进行捻转1min,共留针30min,期间每5min捻转行针1次,每次1min。非穴位组分别在百会、水沟左侧旁开约5mm处进针,避开穴位,手法同穴位针刺。穴位24h组及非穴位24h组在造模后24小时候再针刺1次。采用高效液相检测各组缺血脑组织ATP、ADP、AMP含量,比色法检测Na+-K+-ATP酶、Ca2+-ATP酶含量,real-time PCR检测HIF-1αmRNA及EPOmRNA表达,采用免疫组化检测缺血脑组织GLUT1、GLUT3阳性细胞表达,对上述结果进行综合统计分析。
结果：
1.脑组织ATP、ADP含量在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组ATP、ADP含量降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠ATP、ADP含量较模型2h组升高,经统计学处理,有显著性差异(P<0.01)；与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组ATP、ADP含量较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01),但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。脑组织AMP含量在大鼠脑缺血后2h后即明显升高,与正常组比较,有显著性差异(P<0.01)；模型24h组AMP含量升高更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠AMP含量较模型2h组降低,经统计学处理,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组AMP含量显著低于较模型24h组及非穴位24h组,经统计学处理,有显著性差异(P<0.01),但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
2.脑组织TAN在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组TAN降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠TAN较模型2h组升高,经统计学处理,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组TAN较模型24h组明显升高,经统计学处理,有显著性差异(P<0.01)；穴位24h组TAN较非穴位24h组升高,经统计学处理,有显著性差异(P<0.05)。但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
3.脑组织EC在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组EC降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠EC较模型2h组升高,经统计学处理,有显著性差异(P<0.01)；与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组EC较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01)；但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
4.脑组织Na+-K+-ATP酶含量在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组Na+-K+-ATP酶降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组及非穴位2h组大鼠Na+-K+-ATP酶含量较模型2h组升高,但穴位2h组上升更显著,与模型2h组比较,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.05)。非穴位2h组与模型2h组比较,有显著性差异(P<0.05)。穴位24h组Na+-K+-ATP酶含量较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01)；非穴位24h组与模型24h组比较,无显著性差异。
5.脑组织Ca2+-ATP酶含量在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠Ca2+-ATP酶含量较模型2h组升高,经统计学处理,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组Ca2+-ATP酶含量较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01)；非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
6.各组大鼠缺血侧皮质区域GLUT1免疫阳性物MOD值明显高于正常组(P<0.05～0.01)。穴位2h组较模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.05)；穴位2h组GLUT1阳性表达较非穴位2h组明显增加(P<0.05),而非穴位2h组与模型2h组比较无显著性差异。模型24h组与模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位24h组阳性表达要明显多于模型24h组和非穴位24h,经统计学处理,有显著性差异(P<0.01)。上述结果表明,在缺血后2h～24h之间,GLUT1阳性表达增加；穴位针刺可以明显增强大脑皮质GLUT1阳性表达,而非穴位组表达略有增加,但无显著性差异(P>0.05)。
7.各组大鼠缺血侧皮质区域GLUT3免疫阳性物MOD值明显高于正常组(P<0.05)。穴位2h组较模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位2h组GLUT3阳性表达较非穴位2h组明显增加(P<0.05)；非穴位2h组与模型2h组比较无显著性差异(P>0.05)。模型24h组与模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位24h组阳性表达要明显多于模型组和非穴位24h,经统计学处理,有显著性差异(P<0.05)。上述结果表明,在缺血后2h～24h之间,GLUT3阳性表达增加；穴位针刺可以明显增强大脑皮质GLUT3阳性表达,而非穴位组表达略有增加,但无统计学意义。
8.各组大鼠缺血侧皮质HIF-1αmRNA表达明显高于正常组(P<0.01)。穴位2h组较模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位2h组基因表达较非穴位2h组明显增加(P<0.05)；非穴位2h组与模型2h组比较无显著性差异(P>0.05)。模型24h组与模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01),穴位24h组基因表达要明显多于模型组和非穴位24h,经统计学处理,有显著性差异(P<0.05)。上述结果表明,在缺血后2h～24h之间,HIF-1αmRNA表达增加；穴位针刺可以明显增强大脑皮质HIF-1αmRNA表达,而非穴位组表达略有增加,但无统计学意义(P>0.05)。
9.各组大鼠缺血侧皮质EPOmRNA表达明显高于正常组(P<0.01)。穴位2h组较模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位2h组基因表达较非穴位2h组明显增加(P<0.05)；非穴位2h组与模型2h组比较无显著性差异(P>0.05)。模型24h组与模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位24h组基因表达要明显多于模型组和非穴位24h,经统计学处理,有显著性差异(P<0.05)。上述结果表明,在缺血后2h～24h之间,EPOmRNA表达增加；穴位针刺组可以明显增强大脑皮质EPOmRNA表达,而非穴位组表达略有增加,但无统计学意义(P>0.05)。
结论：
1.急性脑缺血后大鼠脑组织ATP生产及利用均减少,TAN及EC均降低,表明脑缺血后能量代谢障碍,而穴位针刺可以显著改善脑缺血大鼠脑组织能量代谢,发挥抗脑缺血损伤的作用。
2.穴位针刺可以通过改善缺血脑组织的能量代谢,从而恢复Na+-K+-ATP与Ca2+-ATP酶的活性,从而可能通过减少胞内Na+负荷,减轻Ca2+超载,维持了细胞内外Na+、Ca2+稳态,减轻细胞内水肿,影响突触兴奋、传导和递质释放,抑制兴奋性氨基酸等毒性物质的释放,达到脑保护作用。
3.穴位针刺可以上调脑内GLUT1和GLUT3的蛋白表达,增加葡萄糖通过血脑屏障转运入脑,以提高葡萄糖脑转运效率,延续缺氧缺血情况下脑的能量供应,延缓能量耗竭,对抗缺氧缺血的正向反应,减轻缺血缺氧造成的脑损害。
4.穴位针刺能诱导缺血区HIF-1αmRNA表达增加,从而增强EPOmRNA、GLUT1等靶基因的表达,发挥抗缺血损伤的作用。
5.超早期针刺可通过对HIF-1α、GLUT1、GLUT3、EPO等的调节,有效的改善脑缺血后能量代谢,发挥抗脑缺血损伤的作用。
6.穴位针刺对脑缺血大鼠能量代谢及影响脑能量代谢的相关指标的调节作用明显优于非穴位针刺。
Objective:
Cerebrovascular disease has become one of the major diseases that may harm the health and life of Chinese middle-aged and aged people. Acute ischemic cerebral vascular disease takes up 43%～65% of cerebrovascular diseases, with a fatality rate of 15%～5%. Its high incidence, high mortality and high morbidity brings our country and patients heavy economic and social burdens. Due to the first aid is not timely during disease ultra-early phase, many of the clinical patients with cerebral ischemia have their brain cells suffer irreversible damagein after short-term ischemia and hypoxia, ultimately resulting in death or serious sequelae. There will be a positive impact on patients' prognosis, if safe, effective and simple first aid measures are used to effectively protect brain tissue during shortest possible time after the onset. Drug therapy is currently one of the effective means for ischemic brain injury but with a certain toxic and side effects, while acupuncture therapy has been widely used for cerebral vascular disease recovery treatment, and has been become increasingly common treatment to the acute stage of ischemic stroke. An immediate acupuncture treatment given after ischemia gives ischemic cerebral blood flow significant increase and maintain effective local blood supply against ischemia-induced damage, so that makes it possible for re-function after reperfusion; If acupuncture therapy is given during reperfusion period, ischemic cerebral blood supply can also increase and infarct size will significantly reduced so that neurological function was effectively protected. In this study, on the basis of pre-microPET observation that ultra-early acupuncture improves ischemic cerebral glucose metabolism, we are conducting further exploration on the mechanism of ultra-early acupuncture therapy against cerebral ischemia injury.
Methods:
140 female Sprague-Dawley (SD) rats (specific-pathogen free (SPF) grade) of 3 months old, weighing 200-250g, were randomly divided into 7 groups (20 rats in each group):normal group, acupoint 2h group, non-acupoint 2h group, model 2h group, acupoint 24h group, non-acupoint 24h group, model 24h group.10 rats brains in each group were removed after perfusion, with the other 10 were sampled for fresh brain tissue. Acute right middle cerebral artery ischemia was produced in rats with craniotomy and eletrocoagulation on middle cerebral artery. Acupoint groups were treated by acupuncture at "Baihui"and"Shuigou", using reducing method, with 120 twisting per minute, one time every 5 minutes, one minute every time, retaining the needles for 30 minutes. Non-acupoint groups were respectively treated by acupuncture at 5mm away on the left side of "Baihui"and"Shuigou". Acupoint 24h group and non-acupoint 24h group were treated by acupuncture once again after 24 hours.10 rats in each group were examined ATP, ADP, AMP contents in ischemic brain tissue with high-performance liquid chromatography (HPLC), and colorimetry on Na+-K+-ATP enzyme, Ca2+-ATP enzyme levels, and real-time PCR on HIF-1αmRNA, EPOmRNA gene expression, and immunohistochemical to GLUT1, GLUT3 expression of the other 10 rats of each group. Then we conducted a comprehensive statistical analysis of these results.
Results:
1. Compared with normal group, ATP, ADP contents in rats'brain tissue after cerebral ischemia for 2h decreased significantly (P<0.01), and the model 24h group's ATP and ADP content decreased significantly. And compared with model 2h group, acupoint 2h group's ATP, ADP content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a extremely significant difference (P<0.01). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05). Compared with model 24h group and non-acupoint 24h group, acupoint 24h group's ATP, ADP content significantly higher (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05). Compared with normal group, AMP concent in rats' brain tissue after cerebral ischemia for 2h significantly increased significantly (P<0.01), and the model 24h group's AMP content increased more significantly. And compared with model 2h group, acupoint 2h group's AMP content decreased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05). Acupoint 24h group's AMP content was significantly lower than that in model 24h group and non-acupoint 24h group (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
2. Compared with normal group, TAN concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's TAN content decreased significantly. And compared with model 2h group, acupoint 2h group's TAN content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05).Compared with model 24h group and non-acupoint 24h group separately, acupoint 24h group's TAN content significantly highered (P<0.01 and P<0.05), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
3. Compared with normal group, EC concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's EC content decreased significantly. And compared with model 2h group, acupoint 2h group's EC content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05). Compared with model 24h group and non-acupoint 24h group separately, acupoint 24h group's EC content significantly highered (P<0.05 and P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
4. Compared with normal group, Na+-K+-ATP enzyme concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's Na+-K+-ATP enzyme content decreased significantly. And compared with model 2h group, acupoint 2h group's Na+-K+-ATP enzyme content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.05). And there was significant difference between non-acupoint 2h group and model 2h group (P<0.05). Acupoint 24h group's Na+-K+-ATP enzyme content was significantly higher than model 24h group and non-acupoint 24h group (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
5. Compared with normal group, Ca2+-ATP enzyme concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's Ca2+-ATP enzyme content decreased significantly. And compared with model 2h group, acupoint 2h group's Ca2+-ATP enzyme content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05). Acupoint 24h group's Ca2+-ATP enzyme content was significantly higher than model 24h group and non-acupoint 24h group (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
6. GLUT1 immunoreactive material MOD value of each group's ischemic cortex regionalin significantly higher than that in the normal group (P<0.05).And compared with model 2h group, acupoint 2h group's positive expression increased significantly (P<0.05), and compared with non-acupoint 2h group, there was a significant difference (P<0.05). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05). And model 24h groupgroup's positive expression was higher than that of model 2h group (P<0.01). And acupoint 24h group's positive expression significantly higher than model groups and non-acupoint 24h group (P<0.01). These results indicate that GLUT1 expression increased gradually after cerebral ischemia for 2h～24h; Acupoint groups can significantly enhance positive expression of GLUT1 in cerebral cortex, rather than a slight increase in expression of that of non-acupoint groups, but there was no significant difference between them.
7. GLUT3 immunoreactive material MOD value of each group's ischemic cortex regionalin significantly higher than the normal group (P<0.05). And compared with model 2h group, acupoint 2h group's positive expression increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.05). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05).And model 24h groupgroup's positive expression higher than that in model 2h group (P<0.01). And acupoint 24h group's positive expression was significantly higher than that in model groups and non-acupoint 24h group (P<0.05). These results indicate that GLUT3 expression increased gradually after cerebral ischemia for 2h～24h; Acupoint groups can significantly enhance positive expression of GLUT3 in cerebral cortex, rather than a slight increase in expression of non-acupoint groups, but there was no significant difference between them.
8. HIF-1αmRNA gene expression of each group's ischemic cortex region was significantly higher than the normal group (P<0.01).And compared with model 2h group, acupoint 2h group's gene expression increased significantly (P<0.01), and compared with non-acupoint 2h group, there was significant difference (P<0.05). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05).And model 24h group's gene expression higher than model 2h group (P<0.01). And acupoint 24h group's gene expression was significantly higher than model groups and non-acupoint 24h group (P<0.05). These results indicate that HIF-1αmRNA gene expression increased gradually after cerebral ischemia for 2h～24h; Acupoint acupuncture can significantly enhance expression of HIF-1αmRNA gene expression in cerebral cortex, rather than a slight increased in expression of non-acupoint groups, but there was no significant difference between them.
9. EPOmRNA gene expression of each group's ischemic cortex region was significantly higher than the normal group (P<0.01).And compared with model 2h group, acupoint 2h group's gene expression increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference(P<0.05). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05).And model 24h group's gene expression higher than model 2h group (P<0.01). And acupoint 24h group's gene expression significantly higher than model groups and non-acupoint 24h group (P<0.05). These results indicate that EPOmRNA gene expression increased gradually after cerebral ischemia for 2h～24h; Acupoint acupuncture significantly enhanced expression of EPOmRNA gene expression in cerebral cortex, rather than a slight increase in expression of non-acupoint groups, but there was no significant difference between them.
Conclusion:
1. ATP production and utilization in rats' brain tissue were reduced after acute cerebral ischemia, and TAN and EC decreased, indicating an energy metabolism dysfunction, however, situration can be significantly improved by acupoint acupuncture, which plays the role against cerebral ischemia injury.
2. Acupuncture can improve the energy metabolism of ischemic brain tissue, thus restore the Na+-K+-ATP and Ca2+-ATP enzyme activity, and help to reduce the intracellular Na+ load, reduce Ca2+ overload, maintaining Na+, Ca2+ inside and outside cells homeostatic state, which could protect the brain by reducing intracellular edema, affecting synaptic excitement, conduction and transmitter release, inhibiting the release of toxic substances, such as excitatory amino acids, etc.
3. Acupuncture can up-regulate brain GLUT1 and GLUT3 protein expression, increase glucose transport into the brain through the blood-brain barrier, improve the efficiency of glucose transporter in the brain, continue the brain energy supply under hypoxic-ischemic, slow down the energy depletion against hypoxic-ischemic positive response to reduce brain damage caused by ischemia and hypoxia.
4. Acupuncture further induced HIF-1αmRNA gene expression in ischemic area, thereby enhanced expression of target genes such as EPO, GLUT1, etc, so as to play the role against cerebral ischemia injury.
5. Acupoint acupuncture can adjust the content of HIF-1α、GLUT1、GLUT3 and EPO in ischemic area, so as to improve the energy metabolism and play the role against cerebral ischemia at Super Early Stage.
6. Acupoint acupuncture regulation of energy metabolism of ischemic brain tissue and the relevant indicators was better than non-acupoint acupuncture.
脑血管病已成为危害我国中老年人身体健康和生命的主要疾病,急性缺血性脑血管疾病占脑血管疾病的43%-65%,病死率为15%-25%,其高发病率,高死亡率和高致残率给国家及患者带来了沉重的经济和社会负担。临床中许多缺血性脑血管病发病后超早期急救不及时,脑细胞在短期缺血、缺氧后形成了不可逆的损伤,最终造成死亡或恢复期遗留严重后遗症。在发病后最短时间内,使用安全有效、简便易行的急救措施对脑组织进行有效的保护,将对患者的预后产生积极影响。药物疗法仍是目前治疗缺血性脑血管病的有效手段之一,但药物疗法均有一定的毒、副作用,而针刺疗法已广泛应用脑血管病恢复期治疗,并且已被越来越普遍地应用于缺血性中风急性期治疗,在缺血后立即给予针刺治疗则能使局部脑血流显著增加,使缺血组织局部维持有效的血供,对抗缺血引起的损伤；缺血后再灌注期针刺增加局部脑血供,使脑梗死面积显著减小,神经功能得到有效的保护。因此,针刺超早期介入的意义值得重视。本研究在前期采用microPET观察到超早期针刺对脑缺血葡萄糖代谢改善的基础上,进一步探讨超早期针刺抗脑缺血损伤的作用机理,为临床针刺治疗缺血性中风提供一定的实验依据。
方法：
SPF级雌性SD大鼠140只,3月龄,体重200～250g,随机分为7组,正常组、穴位2h组、非穴位2h组、模型2h组、穴位24h组、非穴位24h组、模型24h组,每组各20只,其中10只用来灌注取脑,10只取新鲜脑组织。采用开颅法电凝大脑中动脉造模,制作右侧大鼠大脑中动脉急性脑缺血模型。穴位组取“百会”、“水沟”针刺,以120次／分左右进行捻转1min,共留针30min,期间每5min捻转行针1次,每次1min。非穴位组分别在百会、水沟左侧旁开约5mm处进针,避开穴位,手法同穴位针刺。穴位24h组及非穴位24h组在造模后24小时候再针刺1次。采用高效液相检测各组缺血脑组织ATP、ADP、AMP含量,比色法检测Na+-K+-ATP酶、Ca2+-ATP酶含量,real-time PCR检测HIF-1αmRNA及EPOmRNA表达,采用免疫组化检测缺血脑组织GLUT1、GLUT3阳性细胞表达,对上述结果进行综合统计分析。
结果：
1.脑组织ATP、ADP含量在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组ATP、ADP含量降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠ATP、ADP含量较模型2h组升高,经统计学处理,有显著性差异(P<0.01)；与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组ATP、ADP含量较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01),但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。脑组织AMP含量在大鼠脑缺血后2h后即明显升高,与正常组比较,有显著性差异(P<0.01)；模型24h组AMP含量升高更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠AMP含量较模型2h组降低,经统计学处理,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组AMP含量显著低于较模型24h组及非穴位24h组,经统计学处理,有显著性差异(P<0.01),但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
2.脑组织TAN在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组TAN降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠TAN较模型2h组升高,经统计学处理,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组TAN较模型24h组明显升高,经统计学处理,有显著性差异(P<0.01)；穴位24h组TAN较非穴位24h组升高,经统计学处理,有显著性差异(P<0.05)。但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
3.脑组织EC在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组EC降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠EC较模型2h组升高,经统计学处理,有显著性差异(P<0.01)；与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组EC较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01)；但非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
4.脑组织Na+-K+-ATP酶含量在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组Na+-K+-ATP酶降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组及非穴位2h组大鼠Na+-K+-ATP酶含量较模型2h组升高,但穴位2h组上升更显著,与模型2h组比较,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.05)。非穴位2h组与模型2h组比较,有显著性差异(P<0.05)。穴位24h组Na+-K+-ATP酶含量较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01)；非穴位24h组与模型24h组比较,无显著性差异。
5.脑组织Ca2+-ATP酶含量在大鼠脑缺血后2h后即明显下降,与正常组比较,有显著性差异(P<0.01)；模型24h组降低更显著,与模型2h组比较,有显著性差异(P<0.01)。穴位2h组大鼠Ca2+-ATP酶含量较模型2h组升高,经统计学处理,有显著性差异(P<0.01),与非穴位2h组比较,有显著性差异(P<0.01)。非穴位2h组与模型2h组比较,无显著性差异(P>0.05)。穴位24h组Ca2+-ATP酶含量较模型24h组及非穴位24h组明显升高,经统计学处理,有显著性差异(P<0.01)；非穴位24h组与模型24h组比较,无显著性差异(P>0.05)。
6.各组大鼠缺血侧皮质区域GLUT1免疫阳性物MOD值明显高于正常组(P<0.05～0.01)。穴位2h组较模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.05)；穴位2h组GLUT1阳性表达较非穴位2h组明显增加(P<0.05),而非穴位2h组与模型2h组比较无显著性差异。模型24h组与模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位24h组阳性表达要明显多于模型24h组和非穴位24h,经统计学处理,有显著性差异(P<0.01)。上述结果表明,在缺血后2h～24h之间,GLUT1阳性表达增加；穴位针刺可以明显增强大脑皮质GLUT1阳性表达,而非穴位组表达略有增加,但无显著性差异(P>0.05)。
7.各组大鼠缺血侧皮质区域GLUT3免疫阳性物MOD值明显高于正常组(P<0.05)。穴位2h组较模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位2h组GLUT3阳性表达较非穴位2h组明显增加(P<0.05)；非穴位2h组与模型2h组比较无显著性差异(P>0.05)。模型24h组与模型2h组比较,阳性表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位24h组阳性表达要明显多于模型组和非穴位24h,经统计学处理,有显著性差异(P<0.05)。上述结果表明,在缺血后2h～24h之间,GLUT3阳性表达增加；穴位针刺可以明显增强大脑皮质GLUT3阳性表达,而非穴位组表达略有增加,但无统计学意义。
8.各组大鼠缺血侧皮质HIF-1αmRNA表达明显高于正常组(P<0.01)。穴位2h组较模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位2h组基因表达较非穴位2h组明显增加(P<0.05)；非穴位2h组与模型2h组比较无显著性差异(P>0.05)。模型24h组与模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01),穴位24h组基因表达要明显多于模型组和非穴位24h,经统计学处理,有显著性差异(P<0.05)。上述结果表明,在缺血后2h～24h之间,HIF-1αmRNA表达增加；穴位针刺可以明显增强大脑皮质HIF-1αmRNA表达,而非穴位组表达略有增加,但无统计学意义(P>0.05)。
9.各组大鼠缺血侧皮质EPOmRNA表达明显高于正常组(P<0.01)。穴位2h组较模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位2h组基因表达较非穴位2h组明显增加(P<0.05)；非穴位2h组与模型2h组比较无显著性差异(P>0.05)。模型24h组与模型2h组比较,基因表达明显增加,经统计学处理,有显著性差异(P<0.01)；穴位24h组基因表达要明显多于模型组和非穴位24h,经统计学处理,有显著性差异(P<0.05)。上述结果表明,在缺血后2h～24h之间,EPOmRNA表达增加；穴位针刺组可以明显增强大脑皮质EPOmRNA表达,而非穴位组表达略有增加,但无统计学意义(P>0.05)。
结论：
1.急性脑缺血后大鼠脑组织ATP生产及利用均减少,TAN及EC均降低,表明脑缺血后能量代谢障碍,而穴位针刺可以显著改善脑缺血大鼠脑组织能量代谢,发挥抗脑缺血损伤的作用。
2.穴位针刺可以通过改善缺血脑组织的能量代谢,从而恢复Na+-K+-ATP与Ca2+-ATP酶的活性,从而可能通过减少胞内Na+负荷,减轻Ca2+超载,维持了细胞内外Na+、Ca2+稳态,减轻细胞内水肿,影响突触兴奋、传导和递质释放,抑制兴奋性氨基酸等毒性物质的释放,达到脑保护作用。
3.穴位针刺可以上调脑内GLUT1和GLUT3的蛋白表达,增加葡萄糖通过血脑屏障转运入脑,以提高葡萄糖脑转运效率,延续缺氧缺血情况下脑的能量供应,延缓能量耗竭,对抗缺氧缺血的正向反应,减轻缺血缺氧造成的脑损害。
4.穴位针刺能诱导缺血区HIF-1αmRNA表达增加,从而增强EPOmRNA、GLUT1等靶基因的表达,发挥抗缺血损伤的作用。
5.超早期针刺可通过对HIF-1α、GLUT1、GLUT3、EPO等的调节,有效的改善脑缺血后能量代谢,发挥抗脑缺血损伤的作用。
6.穴位针刺对脑缺血大鼠能量代谢及影响脑能量代谢的相关指标的调节作用明显优于非穴位针刺。
Objective:
Cerebrovascular disease has become one of the major diseases that may harm the health and life of Chinese middle-aged and aged people. Acute ischemic cerebral vascular disease takes up 43%～65% of cerebrovascular diseases, with a fatality rate of 15%～5%. Its high incidence, high mortality and high morbidity brings our country and patients heavy economic and social burdens. Due to the first aid is not timely during disease ultra-early phase, many of the clinical patients with cerebral ischemia have their brain cells suffer irreversible damagein after short-term ischemia and hypoxia, ultimately resulting in death or serious sequelae. There will be a positive impact on patients' prognosis, if safe, effective and simple first aid measures are used to effectively protect brain tissue during shortest possible time after the onset. Drug therapy is currently one of the effective means for ischemic brain injury but with a certain toxic and side effects, while acupuncture therapy has been widely used for cerebral vascular disease recovery treatment, and has been become increasingly common treatment to the acute stage of ischemic stroke. An immediate acupuncture treatment given after ischemia gives ischemic cerebral blood flow significant increase and maintain effective local blood supply against ischemia-induced damage, so that makes it possible for re-function after reperfusion; If acupuncture therapy is given during reperfusion period, ischemic cerebral blood supply can also increase and infarct size will significantly reduced so that neurological function was effectively protected. In this study, on the basis of pre-microPET observation that ultra-early acupuncture improves ischemic cerebral glucose metabolism, we are conducting further exploration on the mechanism of ultra-early acupuncture therapy against cerebral ischemia injury.
Methods:
140 female Sprague-Dawley (SD) rats (specific-pathogen free (SPF) grade) of 3 months old, weighing 200-250g, were randomly divided into 7 groups (20 rats in each group):normal group, acupoint 2h group, non-acupoint 2h group, model 2h group, acupoint 24h group, non-acupoint 24h group, model 24h group.10 rats brains in each group were removed after perfusion, with the other 10 were sampled for fresh brain tissue. Acute right middle cerebral artery ischemia was produced in rats with craniotomy and eletrocoagulation on middle cerebral artery. Acupoint groups were treated by acupuncture at "Baihui"and"Shuigou", using reducing method, with 120 twisting per minute, one time every 5 minutes, one minute every time, retaining the needles for 30 minutes. Non-acupoint groups were respectively treated by acupuncture at 5mm away on the left side of "Baihui"and"Shuigou". Acupoint 24h group and non-acupoint 24h group were treated by acupuncture once again after 24 hours.10 rats in each group were examined ATP, ADP, AMP contents in ischemic brain tissue with high-performance liquid chromatography (HPLC), and colorimetry on Na+-K+-ATP enzyme, Ca2+-ATP enzyme levels, and real-time PCR on HIF-1αmRNA, EPOmRNA gene expression, and immunohistochemical to GLUT1, GLUT3 expression of the other 10 rats of each group. Then we conducted a comprehensive statistical analysis of these results.
Results:
1. Compared with normal group, ATP, ADP contents in rats'brain tissue after cerebral ischemia for 2h decreased significantly (P<0.01), and the model 24h group's ATP and ADP content decreased significantly. And compared with model 2h group, acupoint 2h group's ATP, ADP content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a extremely significant difference (P<0.01). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05). Compared with model 24h group and non-acupoint 24h group, acupoint 24h group's ATP, ADP content significantly higher (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05). Compared with normal group, AMP concent in rats' brain tissue after cerebral ischemia for 2h significantly increased significantly (P<0.01), and the model 24h group's AMP content increased more significantly. And compared with model 2h group, acupoint 2h group's AMP content decreased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05). Acupoint 24h group's AMP content was significantly lower than that in model 24h group and non-acupoint 24h group (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
2. Compared with normal group, TAN concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's TAN content decreased significantly. And compared with model 2h group, acupoint 2h group's TAN content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05).Compared with model 24h group and non-acupoint 24h group separately, acupoint 24h group's TAN content significantly highered (P<0.01 and P<0.05), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
3. Compared with normal group, EC concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's EC content decreased significantly. And compared with model 2h group, acupoint 2h group's EC content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05). Compared with model 24h group and non-acupoint 24h group separately, acupoint 24h group's EC content significantly highered (P<0.05 and P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
4. Compared with normal group, Na+-K+-ATP enzyme concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's Na+-K+-ATP enzyme content decreased significantly. And compared with model 2h group, acupoint 2h group's Na+-K+-ATP enzyme content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.05). And there was significant difference between non-acupoint 2h group and model 2h group (P<0.05). Acupoint 24h group's Na+-K+-ATP enzyme content was significantly higher than model 24h group and non-acupoint 24h group (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
5. Compared with normal group, Ca2+-ATP enzyme concent in rats' brain tissue after cerebral ischemia for 2h significantly decreased significantly (P<0.01). and the model 24h group's Ca2+-ATP enzyme content decreased significantly. And compared with model 2h group, acupoint 2h group's Ca2+-ATP enzyme content increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.01). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05). Acupoint 24h group's Ca2+-ATP enzyme content was significantly higher than model 24h group and non-acupoint 24h group (P<0.01), but no significant difference was observed between non-acupoint 24h group and model 24h group(P>0.05).
6. GLUT1 immunoreactive material MOD value of each group's ischemic cortex regionalin significantly higher than that in the normal group (P<0.05).And compared with model 2h group, acupoint 2h group's positive expression increased significantly (P<0.05), and compared with non-acupoint 2h group, there was a significant difference (P<0.05). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05). And model 24h groupgroup's positive expression was higher than that of model 2h group (P<0.01). And acupoint 24h group's positive expression significantly higher than model groups and non-acupoint 24h group (P<0.01). These results indicate that GLUT1 expression increased gradually after cerebral ischemia for 2h～24h; Acupoint groups can significantly enhance positive expression of GLUT1 in cerebral cortex, rather than a slight increase in expression of that of non-acupoint groups, but there was no significant difference between them.
7. GLUT3 immunoreactive material MOD value of each group's ischemic cortex regionalin significantly higher than the normal group (P<0.05). And compared with model 2h group, acupoint 2h group's positive expression increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference (P<0.05). But no significant difference was observed between non-acupoint 2h group and model 2h group (P>0.05).And model 24h groupgroup's positive expression higher than that in model 2h group (P<0.01). And acupoint 24h group's positive expression was significantly higher than that in model groups and non-acupoint 24h group (P<0.05). These results indicate that GLUT3 expression increased gradually after cerebral ischemia for 2h～24h; Acupoint groups can significantly enhance positive expression of GLUT3 in cerebral cortex, rather than a slight increase in expression of non-acupoint groups, but there was no significant difference between them.
8. HIF-1αmRNA gene expression of each group's ischemic cortex region was significantly higher than the normal group (P<0.01).And compared with model 2h group, acupoint 2h group's gene expression increased significantly (P<0.01), and compared with non-acupoint 2h group, there was significant difference (P<0.05). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05).And model 24h group's gene expression higher than model 2h group (P<0.01). And acupoint 24h group's gene expression was significantly higher than model groups and non-acupoint 24h group (P<0.05). These results indicate that HIF-1αmRNA gene expression increased gradually after cerebral ischemia for 2h～24h; Acupoint acupuncture can significantly enhance expression of HIF-1αmRNA gene expression in cerebral cortex, rather than a slight increased in expression of non-acupoint groups, but there was no significant difference between them.
9. EPOmRNA gene expression of each group's ischemic cortex region was significantly higher than the normal group (P<0.01).And compared with model 2h group, acupoint 2h group's gene expression increased significantly (P<0.01), and compared with non-acupoint 2h group, there was a significant difference(P<0.05). But there was no significant difference between non-acupoint 2h group and model 2h group (P>0.05).And model 24h group's gene expression higher than model 2h group (P<0.01). And acupoint 24h group's gene expression significantly higher than model groups and non-acupoint 24h group (P<0.05). These results indicate that EPOmRNA gene expression increased gradually after cerebral ischemia for 2h～24h; Acupoint acupuncture significantly enhanced expression of EPOmRNA gene expression in cerebral cortex, rather than a slight increase in expression of non-acupoint groups, but there was no significant difference between them.
Conclusion:
1. ATP production and utilization in rats' brain tissue were reduced after acute cerebral ischemia, and TAN and EC decreased, indicating an energy metabolism dysfunction, however, situration can be significantly improved by acupoint acupuncture, which plays the role against cerebral ischemia injury.
2. Acupuncture can improve the energy metabolism of ischemic brain tissue, thus restore the Na+-K+-ATP and Ca2+-ATP enzyme activity, and help to reduce the intracellular Na+ load, reduce Ca2+ overload, maintaining Na+, Ca2+ inside and outside cells homeostatic state, which could protect the brain by reducing intracellular edema, affecting synaptic excitement, conduction and transmitter release, inhibiting the release of toxic substances, such as excitatory amino acids, etc.
3. Acupuncture can up-regulate brain GLUT1 and GLUT3 protein expression, increase glucose transport into the brain through the blood-brain barrier, improve the efficiency of glucose transporter in the brain, continue the brain energy supply under hypoxic-ischemic, slow down the energy depletion against hypoxic-ischemic positive response to reduce brain damage caused by ischemia and hypoxia.
4. Acupuncture further induced HIF-1αmRNA gene expression in ischemic area, thereby enhanced expression of target genes such as EPO, GLUT1, etc, so as to play the role against cerebral ischemia injury.
5. Acupoint acupuncture can adjust the content of HIF-1α、GLUT1、GLUT3 and EPO in ischemic area, so as to improve the energy metabolism and play the role against cerebral ischemia at Super Early Stage.
6. Acupoint acupuncture regulation of energy metabolism of ischemic brain tissue and the relevant indicators was better than non-acupoint acupuncture.
引文
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