去铁敏减轻大鼠短暂性局灶性脑缺血后出血性转换的研究
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摘要
目的:出血性转换(Hemorrhagic transformation,HT)是急性缺血性卒中(Acute ischemia stroke, AIS)后缺血区内出现自发性出血转变,是AIS常见并发症之一。溶栓治疗是目前唯一获得FDA批准的对AIS有效的治疗方法,但是HT是限制溶栓药物应用的主要原因之一,目前尚无有效的防止HT发生的药物。本研究用去铁敏作用于大鼠短暂性局灶性脑缺血模型,探讨其对HT的作用,为探索减少HT的药物治疗提供依据。方法:SD大鼠腹腔注射50%葡萄糖(6ml/kg),注射后15分钟大脑中动脉线栓(MCAO)。MCAO后立即肌注去铁敏(100mg/kg)或等量生理盐水。两小时后拔出线栓,恢复再灌注。分别于4、8、24小时后杀掉大鼠测量脑梗死体积、脑水肿、出血体积、血红蛋白量、血脑屏障通透性,同时评估其死亡率和出血性转换率。结果:去铁敏治疗显著减少MCAO后24小时动物的脑梗死体积、脑水肿程度和死亡率(p<0.05)。MCAO后8小时去铁敏治疗组患侧半球出血量明显少于对照组(p<0.05)。但是去铁敏组与对照组患侧半球之间Evans-blue漏出量无差别。结论:去铁敏治疗减少短暂性局灶性脑缺血伴高血糖大鼠模型动物的死亡率、出血性转换发生率和程度、脑梗死体积、脑肿胀程度,说明对于接受tPA治疗的卒中患者,去铁敏是减少急性缺血性卒中后出血性转换的有潜力的治疗药物。
Hemorrhagic transformation (HT) in ischemic stroke is common and represents almost a natural event in the process of cerebral infarction. There is currently no effective treatment to limit the occurrence or effect of damage of HT after a stroke. Moreover, an increasing rate (10-fold) of intracranial bleeding is reported after the treatment of tissue plasminogen activator (tPA) in stroke patients, which is a major factor limiting the use of tPA to reduce ischemic brain damage in patients.
Deferoxamine (DFX), a high affinity chelator of Fe3+, is used clinically for treatment of primary or secondary hemochromatosis, and experimental studies suggest that DFX may have neuroprotective properties in association with brain ischemia and cerebral vasospasm caused by SAH. In our previous study, we found that DFX reduces hemoglobin-induced brain edema and neurological deficits of intracerebral hemorrhage. However, it is not clear whether DFX can reduce HT after cerebral ischemia.
Objective:
The present study investigated the effects of DFX on mortality rate, HT formation, brain infarct volume, brain edema formation, BBB permeability and neurologic deficit after focal cerebral ischemia with reperfusion in a hyperglycemic rat model.
Methods:
Rats had an injection of 50% glucose (6 mL/kg) intraperitoneally to induce acute hyperglycemia 15minutues before middle cerebral artery occlusion (MCAO). The suture was removed after 2 hours of occlusion. Rats were treated with DFX (100mg/ kg) or vehicle (equivalent volume of normal saline) after MCAO. First, rats were killed at 8 or 24 hours after MCAO. Rat brains were used for histological examination, including the measurements of infarct volume, brain swelling and hemorrhage volume. Second, rat brains were sampled for hemoglobin content determination 24 hours after MCAO. Third, rats were killed 4 hours after MCAO and brains were used for Evans blue content measurement. Fourth, brain water content was determined 8 hours after MCAO. Fifth, the neurological score were determined at days1, 3, 5, 7 and 14 after MCAO. Over all, the effect of rate of mortality and HT formation at 8 hours and 24hours after MCAO was also counted.
Results:
Twenty-four hours after MCAO, the infarct volume in the ipsilateral hemispheres of DFX treated animals was significantly smaller than that in rats treated with vehicles.
Brain swelling occurred in the ipsilateral hemisphere 8 or 24 hours after MCAO. The volumes of ipsilateral hemisphere were larger than the contralateral hemisphere. The ratio of ipsilateral/contralateral basal ganglia was significantly smaller in DFX treated rats than that in vehicle treated rats, but the ratio of ipsilateral/contralateral hemisphere has no significantly different 24 hours after MCAO.
DFX treatment attenuated the death rate 24 hours after MCAO. All the six rats had HT formation with vehicle treatment, but there only 4 out of 6 rats had HT formation with DFX treatment at 8 hours after MCAO. The HT formation happened in the rats treated with DFX is 67% compared to 86% in vehicle trated rats at 24 hours after MCAO.
In all cases, the hemorrhage seen was either petechial or confluent petechial hemorrhage, occurring mostly in the basal ganglia (90.9%) and lateral cortex (59.1%), but occasionally in cingulated cortex (13.6%) and pre-optic area (4.5%). At 8 hours after MCAO, HT formation was more in vehicle group vs. that in DFX-treated rats and the total volume hemorrhage was significantly bigger in rats treated with vehicle vs. that in the rats treated with DFX.
Evans blue content was significantly increased in the ipsilateral hemisphere as compared with the contralateral hemisphere in vehicle animals at 4 hours after MCAO. Although evans-blue content 4 hours after MCAO were higher in DFX-treated animals than that in vehicle animals but has no statistically significant.
DFX did not improve the gross neurological score. By postoperative day 7, all animals had recovered to a similar extent, with the most common residual deficits consisting of gait abnormalities or minor ataxia.
Discussion:
We studied hyperglycemia-induced hemorrhagic conversion in this ischemic model for two main reasons. The first reason is that hyperglycemia is strongly associated with HT and tPA-associated intercerebral hemorrhage, an understanding of how hyperglycemia-induced bleeding might be prevent is clinically relevant. The second reason is the model produces a consistent HT after 2 hours of MCAO with reperfusion. The alternative embolic model with tPA-induced reperfusion is less consistent in both frequency and location of hemorrhage. Other models, such as the collagenase model, which requires intracerebral injections of a toxin that digests tissues, and occlusion of the middle cerebral artery with a thread, are less relevant clinically because they do not reproduce these components of hemorrhagic stroke. In addition, in our previous study we found this model of HT induced by acute heperglycemia is consistent and reliable.
It has been reported by several groups that DFO therapy can decrease infarct volume and brain edema after ischemia/reperfusion. In current study DFX did reduced brain infarction in hyperglycemic animals. Consistent with small infarct size, DFX-treated rats had less basal ganglia swelling. Iron is essential for normal brain function. However, iron overload can cause brain injury after stroke. Ischemia/reperfusion leads to an overproduction of reactive oxygen/nitrogen species, some of them being converted, in the presence of iron, into highly reactive hydroxyl radical species (fenton reaction). DFX could therefore prevent the formation and/or reduce the toxicity of some radicals, thereby reducing cytotoxic and/or vasogenic edema. Although DFX is an iron chelator, it also have other effects. Firstly, DFX has also been described to scavenge directly the hydroxyl radical. Secondly, DFX can inhibits cell cycle transition. Proliferating cells have an essential requirement for iron, and iron chelators block DNA synthesis and halt the cell cycle before the G1/S boundary which is defined as the“safe point”in the cell cycle. Thus it suppress apoptotic death of cell caused by withdrawal of trophic support. Thirdly, DFX activates hypoxia-inducible factor-1 (HIF-1) gene express and induce up-regulation of a number of genes. In addition, DFX decreases the excitatory amino acid levels after hypoxia-ischemia. Which of these mechanisms is operative most likely depends on the nature, duration, and locate of injury-inducing stimulus.
Another important finding is that DFX reduces mortality rate at 24 hours after MCAO in this hyperglycemic stroke model. The death rate in the vehicle group was approximately 24.1%, whereas it was 3.7% among the DFX-treated rats. This lower mortality may result from less hemorrhagic transformation, the smaller infarct and less edema in the DFX-treated group. DFX reduced late death in an animal model of cardiorespiratory arrest. The mechanism may be prevente free-radical-mediated reactions through iron chelation.
The major aim of this study was to examine whether DFX therapy during ischemia would reduce HT after focal cerebral ischemia with reperfusion and indeed DFX did reduce such hemorrhage at 8 hours after MCAO.
Conclusion:
DFX reduces hemorrhagic transformation, infarct volumes, brain swelling ratio in the basal ganglia and mortality at 24 hours after MCAO in hemorrhagic transformation model suggesting early DFX treatment may be useful for patients with stroke.
Hemorrhagic transformation (HT) in ischemic stroke is common and represents almost a natural event in the process of cerebral infarction. There is currently no effective treatment to limit the occurrence or effect of damage of HT after a stroke. Moreover, an increasing rate (10-fold) of intracranial bleeding is reported after the treatment of tissue plasminogen activator (tPA) in stroke patients, which is a major factor limiting the use of tPA to reduce ischemic brain damage in patients.
Deferoxamine (DFX), a high affinity chelator of Fe3+, is used clinically for treatment of primary or secondary hemochromatosis, and experimental studies suggest that DFX may have neuroprotective properties in association with brain ischemia and cerebral vasospasm caused by SAH. In our previous study, we found that DFX reduces hemoglobin-induced brain edema and neurological deficits of intracerebral hemorrhage. However, it is not clear whether DFX can reduce HT after cerebral ischemia.
Objective:
The present study investigated the effects of DFX on mortality rate, HT formation, brain infarct volume, brain edema formation, BBB permeability and neurologic deficit after focal cerebral ischemia with reperfusion in a hyperglycemic rat model.
Methods:
Rats had an injection of 50% glucose (6 mL/kg) intraperitoneally to induce acute hyperglycemia 15minutues before middle cerebral artery occlusion (MCAO). The suture was removed after 2 hours of occlusion. Rats were treated with DFX (100mg/ kg) or vehicle (equivalent volume of normal saline) after MCAO. First, rats were killed at 8 or 24 hours after MCAO. Rat brains were used for histological examination, including the measurements of infarct volume, brain swelling and hemorrhage volume. Second, rat brains were sampled for hemoglobin content determination 24 hours after MCAO. Third, rats were killed 4 hours after MCAO and brains were used for Evans blue content measurement. Fourth, brain water content was determined 8 hours after MCAO. Fifth, the neurological score were determined at days1, 3, 5, 7 and 14 after MCAO. Over all, the effect of rate of mortality and HT formation at 8 hours and 24hours after MCAO was also counted.
Results:
Twenty-four hours after MCAO, the infarct volume in the ipsilateral hemispheres of DFX treated animals was significantly smaller than that in rats treated with vehicles.
Brain swelling occurred in the ipsilateral hemisphere 8 or 24 hours after MCAO. The volumes of ipsilateral hemisphere were larger than the contralateral hemisphere. The ratio of ipsilateral/contralateral basal ganglia was significantly smaller in DFX treated rats than that in vehicle treated rats, but the ratio of ipsilateral/contralateral hemisphere has no significantly different 24 hours after MCAO.
DFX treatment attenuated the death rate 24 hours after MCAO. All the six rats had HT formation with vehicle treatment, but there only 4 out of 6 rats had HT formation with DFX treatment at 8 hours after MCAO. The HT formation happened in the rats treated with DFX is 67% compared to 86% in vehicle trated rats at 24 hours after MCAO.
In all cases, the hemorrhage seen was either petechial or confluent petechial hemorrhage, occurring mostly in the basal ganglia (90.9%) and lateral cortex (59.1%), but occasionally in cingulated cortex (13.6%) and pre-optic area (4.5%). At 8 hours after MCAO, HT formation was more in vehicle group vs. that in DFX-treated rats and the total volume hemorrhage was significantly bigger in rats treated with vehicle vs. that in the rats treated with DFX.
Evans blue content was significantly increased in the ipsilateral hemisphere as compared with the contralateral hemisphere in vehicle animals at 4 hours after MCAO. Although evans-blue content 4 hours after MCAO were higher in DFX-treated animals than that in vehicle animals but has no statistically significant.
DFX did not improve the gross neurological score. By postoperative day 7, all animals had recovered to a similar extent, with the most common residual deficits consisting of gait abnormalities or minor ataxia.
Discussion:
We studied hyperglycemia-induced hemorrhagic conversion in this ischemic model for two main reasons. The first reason is that hyperglycemia is strongly associated with HT and tPA-associated intercerebral hemorrhage, an understanding of how hyperglycemia-induced bleeding might be prevent is clinically relevant. The second reason is the model produces a consistent HT after 2 hours of MCAO with reperfusion. The alternative embolic model with tPA-induced reperfusion is less consistent in both frequency and location of hemorrhage. Other models, such as the collagenase model, which requires intracerebral injections of a toxin that digests tissues, and occlusion of the middle cerebral artery with a thread, are less relevant clinically because they do not reproduce these components of hemorrhagic stroke. In addition, in our previous study we found this model of HT induced by acute heperglycemia is consistent and reliable.
It has been reported by several groups that DFO therapy can decrease infarct volume and brain edema after ischemia/reperfusion. In current study DFX did reduced brain infarction in hyperglycemic animals. Consistent with small infarct size, DFX-treated rats had less basal ganglia swelling. Iron is essential for normal brain function. However, iron overload can cause brain injury after stroke. Ischemia/reperfusion leads to an overproduction of reactive oxygen/nitrogen species, some of them being converted, in the presence of iron, into highly reactive hydroxyl radical species (fenton reaction). DFX could therefore prevent the formation and/or reduce the toxicity of some radicals, thereby reducing cytotoxic and/or vasogenic edema. Although DFX is an iron chelator, it also have other effects. Firstly, DFX has also been described to scavenge directly the hydroxyl radical. Secondly, DFX can inhibits cell cycle transition. Proliferating cells have an essential requirement for iron, and iron chelators block DNA synthesis and halt the cell cycle before the G1/S boundary which is defined as the“safe point”in the cell cycle. Thus it suppress apoptotic death of cell caused by withdrawal of trophic support. Thirdly, DFX activates hypoxia-inducible factor-1 (HIF-1) gene express and induce up-regulation of a number of genes. In addition, DFX decreases the excitatory amino acid levels after hypoxia-ischemia. Which of these mechanisms is operative most likely depends on the nature, duration, and locate of injury-inducing stimulus.
Another important finding is that DFX reduces mortality rate at 24 hours after MCAO in this hyperglycemic stroke model. The death rate in the vehicle group was approximately 24.1%, whereas it was 3.7% among the DFX-treated rats. This lower mortality may result from less hemorrhagic transformation, the smaller infarct and less edema in the DFX-treated group. DFX reduced late death in an animal model of cardiorespiratory arrest. The mechanism may be prevente free-radical-mediated reactions through iron chelation.
The major aim of this study was to examine whether DFX therapy during ischemia would reduce HT after focal cerebral ischemia with reperfusion and indeed DFX did reduce such hemorrhage at 8 hours after MCAO.
Conclusion:
DFX reduces hemorrhagic transformation, infarct volumes, brain swelling ratio in the basal ganglia and mortality at 24 hours after MCAO in hemorrhagic transformation model suggesting early DFX treatment may be useful for patients with stroke.
引文
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