去铁敏对大鼠脑出血后葡萄糖代谢影响的研究
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摘要
背景与目的:
脑出血(Intracerebral hemorrhage,ICH)是神经系统的常见疾病,约占全部卒中的10-30%,死亡率及致残率极高。尽管及时清除血肿,防止其扩大对极少数患者可能有一定的疗效,但总体效果却不尽人意。因此,至今为止对脑出血尚无明确有效的治疗手段。大鼠脑出血后存在铁离子的长期潴留,血红蛋白及其降解产物,尤其是铁离子,参与了脑出血后的迟发性脑损伤过程。去铁敏,一种铁离子螯合剂,可以减轻脑出血导致的脑水肿、神经元死亡、脑萎缩及神经功能减退等等。葡萄糖是脑内唯一的供能物质,它的水平与神经元的活性程度密切相关。尽管已有大量的研究显示铁离子在脑水肿形成以及在脑出血后迟发性脑损伤中有重要作用,但很少有资料研究脑出血后铁离子与脑内局部葡萄糖代谢之间的关系,以及用铁离子螯合剂——去铁敏治疗后,葡萄糖代谢的变化情况。目前,定量测定活体内葡萄糖代谢率的最有效方法为放射自显影技术,即用~(18)F-FDG作为示踪剂进行放射自显影,它能无创动态定量地观察到各部分脑组织葡萄糖的代谢变化情况。小动物PET(small animal PET,MicroPET)是专门为小动物的PET显像研究而设计制造的,其分辨率更高。为了更进一步提高分辨率,本研究将MicroPET与MRI影像融合,使解剖形态与生化过程相结合,能更精确观察大鼠脑出血后基底节区的葡萄糖代谢变化。
研究方法:
通过大鼠自体血注入大脑尾状核建立脑出血实验动物模型,并将动物随机分为3组:去铁敏治疗组、对照组和假手术组(n=6只)。去铁敏治疗组动物在术后2h开始腹腔注射去铁敏100mg/kg,以后间隔12小时注射一次,连续7天。对照组在相应时间腹腔注射等量生理盐水。所有大鼠分别在术前、术后1d、3d、7d、14d和28d进行MRI和MicroPET扫描,采用MicroPET和MRI融合技术,观察大鼠脑出血前后基底节区葡萄糖代谢变化以及脑内血肿在梯度回波T_2~*WI序列的演变过程,并在相应时间点对大鼠进行神经功能学评分。同时在此基础上,观察去铁敏治疗后对脑内局部葡萄糖代谢的影响,并检测脑出血后28d时血肿周围淀粉样前体蛋白(amyloid precusor protein,APP)和葡萄糖转运蛋白-1(glucosetransporter-1,GLUT-1)的表达情况。
结果:
大鼠脑出血后可出现严重的神经功能缺失症状。与假手术组相比,大鼠脑出血后1d注血侧基底节葡萄糖代谢水平较对侧明显下降,随着时间的延长,注射侧基底节葡萄糖代谢率缓慢提高,但至28d时两侧基底节的葡萄糖代谢水平仍有差异。大鼠T_2~*WI扫描发现脑出血后急性期血肿部位表现为边界清楚的低信号环,内部为略高信号或低信号区内混杂小点、斑片状高信号;慢性期(28d)表现为边界清楚的均质低信号,提示了T_2~*WI可清晰显示脑内含铁血黄素沉积区域,且与血肿大小及范围一致。与对照组相比,经去铁敏治疗可显著提高注射侧基底节葡萄糖的代谢水平,缩小含铁血黄素沉积范围,改善神经功能缺失症状,且持续时间长。免疫组化结果示术后28d,血肿周围仍有APP染色阳性细胞表达,提示在脑出血后期,血肿周围仍存在轴突损伤,而出血侧GLUT-I的表达较对侧有减少的趋势。
结论:
1.脑出血后血肿周围存在葡萄糖代谢水平明显降低。
2.去铁敏能显著缩小含铁血黄素沉积范围,提高葡萄糖代谢水平,改善大鼠脑出血后的神经功能,提示铁离子潴留可能参与了这一过程。
3.脑出血后28d注射测基底节仍有淀粉样前体蛋白表达,提示在脑出血后期仍存在轴突损伤,其可能是导致ICH后葡萄糖代谢水平下降的重要原因之一。
Background and Purpose:
Intracerebral hemorrhage(ICH) is a subtype of stroke with high morbidity and mortality accounting for about 10-30%of all strokes.Although the hematoma in humans gradually resolves,the neurological deficits in ICH patients are usually permanent and disabling.At present,there is no specific treatment for spontaneous intracerebral hemorrhage beyond supportive medical care.Several studies suggest that iron overload occurs in the brain following ICH and,an iron chelator,deferoxamine, can reduce ICH-induced brain damage,neuron death,brain atrophy,as well as neurological deficits,which suggests that iron plays an important part in brain injury after ICH.However,there is little known about the relationship between local glucose metabolism in brain and iron overload after ICH and the role of deferoxamine(DFX). The level of glucose metabolism correlates with the degree of neuronal activity.So far, the best method to make glucose quantitation in vivo is autoradiography using the tracer of 2-[18F]-fluoro-2-deoxy-D-glucose(FDG),which is the well-known radiotracer that has been frequently used as a marker of metabolic activity for glucose.Small animal Positron emission tomography(MicroPET) is a noninvasive imaging technique that allows quantitative in vivo determination of the rates of various physiologic and biochemical process with minimal invasiveness.In our study,we have co-registered a single MRI template with PET images,which greatly improves the interpretation of the PET images.
Methods:
A ICH model was set up by infusion of 100μl autologous blood into right basal ganglia of Sprague-Dawley rat(Wt:300 to 350 g).Rats were randomly assigned to three groups: ICH+Vehicle,ICH+DFX and sham group(n=6).In ICH+DFX group,rats received deferoxamine treatment(100mg/kg,i.p.,2 hour after ICH and at 12-hour intervals thereafter).The other two groups received the same amount of vehicle.All animals underwent 7 times MRI and MicroPET scan at pretest of ICH and 1,3,7,14,28 days after ICH,then the PET and MRI images were co-registered using ASIPro VM software to measure the glucose metabolism.Besides,we also observed the turnover of hematoma in Gradient Recalled Echo T_2~*WI sequential as well as the behavioral testings at the time point.Then we examined the effect of deferoxamine therapy on glucose metabolism after ICH and,detected amyloid precusor protein(APP) and glucose transporter-1(GLUT-1) immunoreactivity 28d after ICH.
Results:
Our results demonstrated that glucose metabolism in the hematoma area underwent a severe decrease 1 day after ICH and,the discrepancy between the basal ganglia in ipsilateral side and contralateral side continued to 28 days.Hematoma areas appeared as homogeneous patchy hypointension or in homogeneous hypointensity with punctuate hyperintensity on GRE-T_2~*WI.The accumulation of hemosiderin displayed clearly according to the brain sample.Treatment with deferoxamine not only significantly ameliorated the decrease in cerebral metabolic rate of glucose in the perihematoma,but also minimized the hemosiderin deposition and,improved ICH-induced neurological deficits.Effects of DFX treatment on metabolic activity of glucose is persist a long period.We also found the expression of APP increased and a declined tendency of GLUT-1 in the boundary zone of the hematoma.
Conclusion:
1.Glucose metabolism in the hematoma area underwent a severe decrease after ICH.
2.Treatment with deferoxamine not only significantly ameliorated the decrease in cerebral metabolic rate of glucose in the perihematoma,but also minimized the hemosiderin deposition and,improved ICH-induced neurological deficits,which prompted that iron overload might participate in the processes.
3.APP-positive cells could be found at 28d after ICH,which indicated the presence of axons injuries and might result in the decrease of metabolic activity of glucose in the right basal ganglia of rat after ICH.
脑出血(Intracerebral hemorrhage,ICH)是神经系统的常见疾病,约占全部卒中的10-30%,死亡率及致残率极高。尽管及时清除血肿,防止其扩大对极少数患者可能有一定的疗效,但总体效果却不尽人意。因此,至今为止对脑出血尚无明确有效的治疗手段。大鼠脑出血后存在铁离子的长期潴留,血红蛋白及其降解产物,尤其是铁离子,参与了脑出血后的迟发性脑损伤过程。去铁敏,一种铁离子螯合剂,可以减轻脑出血导致的脑水肿、神经元死亡、脑萎缩及神经功能减退等等。葡萄糖是脑内唯一的供能物质,它的水平与神经元的活性程度密切相关。尽管已有大量的研究显示铁离子在脑水肿形成以及在脑出血后迟发性脑损伤中有重要作用,但很少有资料研究脑出血后铁离子与脑内局部葡萄糖代谢之间的关系,以及用铁离子螯合剂——去铁敏治疗后,葡萄糖代谢的变化情况。目前,定量测定活体内葡萄糖代谢率的最有效方法为放射自显影技术,即用~(18)F-FDG作为示踪剂进行放射自显影,它能无创动态定量地观察到各部分脑组织葡萄糖的代谢变化情况。小动物PET(small animal PET,MicroPET)是专门为小动物的PET显像研究而设计制造的,其分辨率更高。为了更进一步提高分辨率,本研究将MicroPET与MRI影像融合,使解剖形态与生化过程相结合,能更精确观察大鼠脑出血后基底节区的葡萄糖代谢变化。
研究方法:
通过大鼠自体血注入大脑尾状核建立脑出血实验动物模型,并将动物随机分为3组:去铁敏治疗组、对照组和假手术组(n=6只)。去铁敏治疗组动物在术后2h开始腹腔注射去铁敏100mg/kg,以后间隔12小时注射一次,连续7天。对照组在相应时间腹腔注射等量生理盐水。所有大鼠分别在术前、术后1d、3d、7d、14d和28d进行MRI和MicroPET扫描,采用MicroPET和MRI融合技术,观察大鼠脑出血前后基底节区葡萄糖代谢变化以及脑内血肿在梯度回波T_2~*WI序列的演变过程,并在相应时间点对大鼠进行神经功能学评分。同时在此基础上,观察去铁敏治疗后对脑内局部葡萄糖代谢的影响,并检测脑出血后28d时血肿周围淀粉样前体蛋白(amyloid precusor protein,APP)和葡萄糖转运蛋白-1(glucosetransporter-1,GLUT-1)的表达情况。
结果:
大鼠脑出血后可出现严重的神经功能缺失症状。与假手术组相比,大鼠脑出血后1d注血侧基底节葡萄糖代谢水平较对侧明显下降,随着时间的延长,注射侧基底节葡萄糖代谢率缓慢提高,但至28d时两侧基底节的葡萄糖代谢水平仍有差异。大鼠T_2~*WI扫描发现脑出血后急性期血肿部位表现为边界清楚的低信号环,内部为略高信号或低信号区内混杂小点、斑片状高信号;慢性期(28d)表现为边界清楚的均质低信号,提示了T_2~*WI可清晰显示脑内含铁血黄素沉积区域,且与血肿大小及范围一致。与对照组相比,经去铁敏治疗可显著提高注射侧基底节葡萄糖的代谢水平,缩小含铁血黄素沉积范围,改善神经功能缺失症状,且持续时间长。免疫组化结果示术后28d,血肿周围仍有APP染色阳性细胞表达,提示在脑出血后期,血肿周围仍存在轴突损伤,而出血侧GLUT-I的表达较对侧有减少的趋势。
结论:
1.脑出血后血肿周围存在葡萄糖代谢水平明显降低。
2.去铁敏能显著缩小含铁血黄素沉积范围,提高葡萄糖代谢水平,改善大鼠脑出血后的神经功能,提示铁离子潴留可能参与了这一过程。
3.脑出血后28d注射测基底节仍有淀粉样前体蛋白表达,提示在脑出血后期仍存在轴突损伤,其可能是导致ICH后葡萄糖代谢水平下降的重要原因之一。
Background and Purpose:
Intracerebral hemorrhage(ICH) is a subtype of stroke with high morbidity and mortality accounting for about 10-30%of all strokes.Although the hematoma in humans gradually resolves,the neurological deficits in ICH patients are usually permanent and disabling.At present,there is no specific treatment for spontaneous intracerebral hemorrhage beyond supportive medical care.Several studies suggest that iron overload occurs in the brain following ICH and,an iron chelator,deferoxamine, can reduce ICH-induced brain damage,neuron death,brain atrophy,as well as neurological deficits,which suggests that iron plays an important part in brain injury after ICH.However,there is little known about the relationship between local glucose metabolism in brain and iron overload after ICH and the role of deferoxamine(DFX). The level of glucose metabolism correlates with the degree of neuronal activity.So far, the best method to make glucose quantitation in vivo is autoradiography using the tracer of 2-[18F]-fluoro-2-deoxy-D-glucose(FDG),which is the well-known radiotracer that has been frequently used as a marker of metabolic activity for glucose.Small animal Positron emission tomography(MicroPET) is a noninvasive imaging technique that allows quantitative in vivo determination of the rates of various physiologic and biochemical process with minimal invasiveness.In our study,we have co-registered a single MRI template with PET images,which greatly improves the interpretation of the PET images.
Methods:
A ICH model was set up by infusion of 100μl autologous blood into right basal ganglia of Sprague-Dawley rat(Wt:300 to 350 g).Rats were randomly assigned to three groups: ICH+Vehicle,ICH+DFX and sham group(n=6).In ICH+DFX group,rats received deferoxamine treatment(100mg/kg,i.p.,2 hour after ICH and at 12-hour intervals thereafter).The other two groups received the same amount of vehicle.All animals underwent 7 times MRI and MicroPET scan at pretest of ICH and 1,3,7,14,28 days after ICH,then the PET and MRI images were co-registered using ASIPro VM software to measure the glucose metabolism.Besides,we also observed the turnover of hematoma in Gradient Recalled Echo T_2~*WI sequential as well as the behavioral testings at the time point.Then we examined the effect of deferoxamine therapy on glucose metabolism after ICH and,detected amyloid precusor protein(APP) and glucose transporter-1(GLUT-1) immunoreactivity 28d after ICH.
Results:
Our results demonstrated that glucose metabolism in the hematoma area underwent a severe decrease 1 day after ICH and,the discrepancy between the basal ganglia in ipsilateral side and contralateral side continued to 28 days.Hematoma areas appeared as homogeneous patchy hypointension or in homogeneous hypointensity with punctuate hyperintensity on GRE-T_2~*WI.The accumulation of hemosiderin displayed clearly according to the brain sample.Treatment with deferoxamine not only significantly ameliorated the decrease in cerebral metabolic rate of glucose in the perihematoma,but also minimized the hemosiderin deposition and,improved ICH-induced neurological deficits.Effects of DFX treatment on metabolic activity of glucose is persist a long period.We also found the expression of APP increased and a declined tendency of GLUT-1 in the boundary zone of the hematoma.
Conclusion:
1.Glucose metabolism in the hematoma area underwent a severe decrease after ICH.
2.Treatment with deferoxamine not only significantly ameliorated the decrease in cerebral metabolic rate of glucose in the perihematoma,but also minimized the hemosiderin deposition and,improved ICH-induced neurological deficits,which prompted that iron overload might participate in the processes.
3.APP-positive cells could be found at 28d after ICH,which indicated the presence of axons injuries and might result in the decrease of metabolic activity of glucose in the right basal ganglia of rat after ICH.
引文
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