脑卒中后早期运动训练促进脑功能修复的作用及其机制研究
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摘要
研究背景：运动训练是一种能有效促进脑卒中后神经功能恢复的康复训练方案。动物研究已经表明,在脑卒中后中后期开始介入的运动训练可以增加动物行为功能表现,而且不会加重脑损伤。最近的临床研究结果发现,在脑卒中后早期(48小时以内)介入积极地康复治疗方案也有利于患者功能恢复,然而这种早期康复的作用却缺乏有力的实验证据,涉及的分子机制也不清楚。因此,我们通过大鼠大脑中动脉栓塞模型模拟脑卒中,在模型建立后24小时介入强度逐步增加的运动康复训练,通过多种行为学和组织学、分子生物学方法,从神经炎性反应和脑血流的角度研究了脑卒中早期运动训练对脑功能修复的作用和分子机制。
研究方法：采用SD大鼠,建立60分钟的脑缺血再灌注模型,在脑缺血后24小时介入强度逐步增加的跑台运动训练(从第一天5米/分钟到第三天的12米/分钟,并持续至实验结束),同时设置缺血对照组和假手术组。在术后第3-21天(每隔3天)分别采用神经功能缺失评分评价动物神经功能缺失症状,使用foot-fault的方法评估动物的运动协调能力,用adhesive remove的方法测试动物的感觉整合能力,利用beam balance法检测大鼠的平衡能力；术后第21-25天采用Morris水迷宫检测大鼠的空间学习和记忆能力。同时,我们还通过检测脑梗死体积、脑水肿和血脑屏障渗透性研究了早期运动训练对脑组织的保护作用,并分别采用实时定量PCR和免疫荧光的方法检测了脑缺血早期神经炎性因子的转录表达和对内源性炎性细胞的激活。最后我们还通过激光散斑脑血流成像技术评估运动训练对缺血皮层脑血流灌注量的影响。
研究结果：
(1)相比于缺血对照组,运动训练组的大鼠神经功能缺失症状得到明显缓解,运动协调能力也得到了更好的恢复,空间学习和记忆能力也得到了很大的提高,但是对于感觉能力和平衡能力的恢复没有显著的促进作用；
(2)与改善行为学结果一致的是,运动训练组显著减少缺血大鼠的脑梗死体积、脑水含量和血脑屏障的破坏；
(3)进一步研究发现,运动训练明显抑制了脑缺血早期的神经炎性因子(IL-1α, IL1-β, IL-6, iNOS, COX2, TNFα)和细胞粘附分子(ICAM-1.VCAM-1)的转录表达,抑制了脑内星形胶质细胞和小胶质细胞的过度激活；
(4)与这些结果相一致的是,相比于缺血对照组的大鼠,脑缺血后连续14天的运动训练显著促进了缺血脑皮层的血流灌注量。
结论：我们的结果为脑卒中早期运动训练的神经保护作用提供了有力的实验证据,这种神经保护作用的机制可能与缓解缺血早期神经炎性反应、减轻血脑屏障和脑水肿,以及促进缺血皮层脑血流灌注有关。其中涉及的具体的分子机制仍需要进一步的深入研究。
Background:Exercise is a clinically promising strategy for promoting neurological recovery in ischemic stroke patients. In animal studies, enforced delayed excises initiated after stroke appear to be able to enhance functional recovery without deteriorating ischemic brain lesions. However, recent clinical data suggest that early initiated exercise within48hour after stroke may offer beneficial effects in patients; whereas the evidence for a neuroprotective effect of early exercise in experimental stroke is scant and the underlying mechanism for early exercise-afforded neuroprotection is unknown. In the present study, we have investigated the effect of early exercise on brain damage, inflammation, the change of cerebral of brain blood flow in ischemia cortex, and neurobehavioral outcomes in a rat model of transient focal cerebral ischemia.
Methods:Stroke was induced in adult male Sprague-Dawley rats by middle cerebral artery occlusion for60min, and the animals were then randomly assigned to early exercise or non-excise groups. Beginning at24hour after ischemia, exercise was induced by enforced treadmill training on a daily basis for a maximum of14days. The daily excises gradually reached the full amount (12meters/min for30min) at the3rd day. For outcome assessments, neurological scores and sensorimotor deficits (foot fault test and adhesive remove test) were determined at3-21days after ischemia, and the ability of feeling and balance were assessed by adhesive remove and beam balance at same time point, while spatial learning and memory were measured by Morris water maze at21-25days after ischemia. In additional rats, infarct volume, brain edema (wet and dry weight), and blood brain barrier integrity (Evans blue extravasations) were assessed at7th days after ischemia. The expression of pro-inflammatory cytokines (mRNAs) and cell adhesion proteins (ICAM and VCAM) was measured at3rd,5th and7th days after ischemia using real-time PCR, and the reactive astrocytes and microglia cells were determined by immunofluorescence staining. In order to detect the change of cerebral of brain blood flow in ischemia cortex after continued treadmill training of two weeks, the laser speckle flowmetry was used.
Results:(1) Compared to non-excise stroke animals, animals received early exercise exhibited significantly improved neurological scores and performed significantly better in the foot fault tests (p<0.05vs. non-excise controls,), but not in the adhesive removal tests and beam balance tests. Animals under early exercise also showed significantly improved study and working memory in Morris water maze compared to non-excise animals (p<0.05).(2) In consistent with the early improvement of functional outcomes, animals under early exercise had significantly reduced infarct volume, brain water content, and blood brain barrier damage at7th days after ischemia compared to non-excise animals (p<0.05).(3) Moreover, the neuroprotection afforded by early exercise was associated with significantly reduced expression of proinflammatory cytokines (IL-lα, IL1-β, IL-6, iNOS, COX2, and TNFα) and cell adhesion molecules at3,5and7days after ischemia (p<0.05vs. non-excise controls), respectively.mean time, early exercise inhibited the activation of astrocytes and microglia cells at3and7days after ischemia.(4)Consisted with these, early exercise significantly improved the CBF in ischemic region compared with the non-exercise group.
Conclusion:Our results provide novel evidence that early initiated exercise confers marked neuroprotection against focal ischemic brain injury in rats. This neuroprotection by early exercise is associated with the attenuation of pro-inflammatory reactions, brain edema, and blood brain barrier damage, and improved cerebral blood flow in the ischemia cortex after ischemia and reperfusion. Further work is required to elucidate the precise underlying mechanisms.
研究方法：采用SD大鼠,建立60分钟的脑缺血再灌注模型,在脑缺血后24小时介入强度逐步增加的跑台运动训练(从第一天5米/分钟到第三天的12米/分钟,并持续至实验结束),同时设置缺血对照组和假手术组。在术后第3-21天(每隔3天)分别采用神经功能缺失评分评价动物神经功能缺失症状,使用foot-fault的方法评估动物的运动协调能力,用adhesive remove的方法测试动物的感觉整合能力,利用beam balance法检测大鼠的平衡能力；术后第21-25天采用Morris水迷宫检测大鼠的空间学习和记忆能力。同时,我们还通过检测脑梗死体积、脑水肿和血脑屏障渗透性研究了早期运动训练对脑组织的保护作用,并分别采用实时定量PCR和免疫荧光的方法检测了脑缺血早期神经炎性因子的转录表达和对内源性炎性细胞的激活。最后我们还通过激光散斑脑血流成像技术评估运动训练对缺血皮层脑血流灌注量的影响。
研究结果：
(1)相比于缺血对照组,运动训练组的大鼠神经功能缺失症状得到明显缓解,运动协调能力也得到了更好的恢复,空间学习和记忆能力也得到了很大的提高,但是对于感觉能力和平衡能力的恢复没有显著的促进作用；
(2)与改善行为学结果一致的是,运动训练组显著减少缺血大鼠的脑梗死体积、脑水含量和血脑屏障的破坏；
(3)进一步研究发现,运动训练明显抑制了脑缺血早期的神经炎性因子(IL-1α, IL1-β, IL-6, iNOS, COX2, TNFα)和细胞粘附分子(ICAM-1.VCAM-1)的转录表达,抑制了脑内星形胶质细胞和小胶质细胞的过度激活；
(4)与这些结果相一致的是,相比于缺血对照组的大鼠,脑缺血后连续14天的运动训练显著促进了缺血脑皮层的血流灌注量。
结论：我们的结果为脑卒中早期运动训练的神经保护作用提供了有力的实验证据,这种神经保护作用的机制可能与缓解缺血早期神经炎性反应、减轻血脑屏障和脑水肿,以及促进缺血皮层脑血流灌注有关。其中涉及的具体的分子机制仍需要进一步的深入研究。
Background:Exercise is a clinically promising strategy for promoting neurological recovery in ischemic stroke patients. In animal studies, enforced delayed excises initiated after stroke appear to be able to enhance functional recovery without deteriorating ischemic brain lesions. However, recent clinical data suggest that early initiated exercise within48hour after stroke may offer beneficial effects in patients; whereas the evidence for a neuroprotective effect of early exercise in experimental stroke is scant and the underlying mechanism for early exercise-afforded neuroprotection is unknown. In the present study, we have investigated the effect of early exercise on brain damage, inflammation, the change of cerebral of brain blood flow in ischemia cortex, and neurobehavioral outcomes in a rat model of transient focal cerebral ischemia.
Methods:Stroke was induced in adult male Sprague-Dawley rats by middle cerebral artery occlusion for60min, and the animals were then randomly assigned to early exercise or non-excise groups. Beginning at24hour after ischemia, exercise was induced by enforced treadmill training on a daily basis for a maximum of14days. The daily excises gradually reached the full amount (12meters/min for30min) at the3rd day. For outcome assessments, neurological scores and sensorimotor deficits (foot fault test and adhesive remove test) were determined at3-21days after ischemia, and the ability of feeling and balance were assessed by adhesive remove and beam balance at same time point, while spatial learning and memory were measured by Morris water maze at21-25days after ischemia. In additional rats, infarct volume, brain edema (wet and dry weight), and blood brain barrier integrity (Evans blue extravasations) were assessed at7th days after ischemia. The expression of pro-inflammatory cytokines (mRNAs) and cell adhesion proteins (ICAM and VCAM) was measured at3rd,5th and7th days after ischemia using real-time PCR, and the reactive astrocytes and microglia cells were determined by immunofluorescence staining. In order to detect the change of cerebral of brain blood flow in ischemia cortex after continued treadmill training of two weeks, the laser speckle flowmetry was used.
Results:(1) Compared to non-excise stroke animals, animals received early exercise exhibited significantly improved neurological scores and performed significantly better in the foot fault tests (p<0.05vs. non-excise controls,), but not in the adhesive removal tests and beam balance tests. Animals under early exercise also showed significantly improved study and working memory in Morris water maze compared to non-excise animals (p<0.05).(2) In consistent with the early improvement of functional outcomes, animals under early exercise had significantly reduced infarct volume, brain water content, and blood brain barrier damage at7th days after ischemia compared to non-excise animals (p<0.05).(3) Moreover, the neuroprotection afforded by early exercise was associated with significantly reduced expression of proinflammatory cytokines (IL-lα, IL1-β, IL-6, iNOS, COX2, and TNFα) and cell adhesion molecules at3,5and7days after ischemia (p<0.05vs. non-excise controls), respectively.mean time, early exercise inhibited the activation of astrocytes and microglia cells at3and7days after ischemia.(4)Consisted with these, early exercise significantly improved the CBF in ischemic region compared with the non-exercise group.
Conclusion:Our results provide novel evidence that early initiated exercise confers marked neuroprotection against focal ischemic brain injury in rats. This neuroprotection by early exercise is associated with the attenuation of pro-inflammatory reactions, brain edema, and blood brain barrier damage, and improved cerebral blood flow in the ischemia cortex after ischemia and reperfusion. Further work is required to elucidate the precise underlying mechanisms.
引文
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