脑出血模型中铁离子潴留对迟发性脑损伤的作用机制研究
摘要
研究目的:
脑出血后血红蛋白降解释放的铁离子在急性期过后仍长期滞留于脑内。本研究拟观察脑出血后潴留于脑内的铁离子是否对脑组织产生迟发性损伤,并对其机制进行探索。
研究方法:
本研究分两部分。第一部分:通过大鼠自体血基底节模型和大鼠海马氯化亚铁注射模型,观察是否存在迟发性脑萎缩并进行FJC染色检测建模后2周时是否仍存在神经元变性。同时,在不同时间点应用Perl's染色观察铁离子脑内潴留情况,应用OX-6染色观察小胶质细胞激活情况,运用磷酸化P65染色观察NF-κB活化情况,运用铁蛋白/OX-42复染观察脑出血后铁蛋白在小胶质细胞中的表达情况。并观察铁离子螯合和米诺环素治疗对迟发性脑萎缩和神经功能的影响。第二部分:进行小胶质细胞和神经元培养。通过OX-6染色和磷酸化P65染色分别观察Fe~(2+)对小胶质细胞的激活作用和对小胶质细胞NF-κB活化的影响。通过Fe~(2+)直接处理神经元和Fe~(2+)处理小胶质细胞后所得上清再处理神经元观察Fe~(2+)对神经元的作用途径,明确小胶质细胞在其中的作用,并给予米诺环素进行干预治疗。
结果:
大鼠脑出血模型中12周仍存在铁离子潴留和出血侧铁蛋白染色增强,复染提示脑出血后4周后铁蛋白轻/重链主要表达于小胶质细胞。脑出血后2周时,出血侧基底节未见明显萎缩,在4周时萎缩出现,到8周时则更显著。FJC染色提示2周时,血肿侧仍有变性神经元存在。在海马FeCl_2注射模型中也能在2周时检测到变性神经元。铁离子螯合治疗可以有效减轻脑出血后的迟发性脑萎缩。小胶质细胞激活和NF-κB的活化现象在脑出血模型和海马FeCl_2模型中都存在并至少持续至建模后2周。米诺环素可以减轻脑出血后的迟发性脑萎缩。Fe~(2+)能直接激活培养小胶质细胞。Fe~(2+)直接作用于培养神经元,不能引起其LDH水平的增高,而Fe~(2+)处理后的小胶质细胞进一步孵育产生的上清对神经元具有损伤作用,应用米诺环素则能有效逆转这种损伤,米诺环素还能抑制小胶质细胞激活和NF-κB的活化。
结论:
1)大鼠脑出血模型中存在迟发性脑损伤。2)Fe~(2+)可以通过激活小胶质细胞进而引起神经细胞的死亡。3)脑出血后迟发性脑损伤与铁离子长期潴留于脑内有关。长期潴留于脑内的铁离子可能通过小胶质细胞激活引起神经元的迟发性变性死亡。NF-κB活化可能参与了这一过程。研究不仅揭示脑出血后存在的迟发性损伤这一病理现象并对其机制进行了探讨,同时也为今后临床治疗提供了新的思路。
Purpose:
Persistent iron retention is observed after intracerebral hemorrhage(ICH),while weather it makes delayed injury to brain remains unknown.The present study focuses on the possible effects and mechanism of accumulated iron on brain tissues during chronic stage of ICH.
Methods:
The study was including 2 parts.Part 1:A ICH model was set up by infusion of 100μl autologous blood into right basal ganglia of SD rat and a ferrous iron model was set up by insertion of 30μl ferrous chloride of 10mM into right hippocampus of rat seperately.Delayed brain atrophy was assessed and Fluoro-Jade C(FJC) staining at 2weeks after ICH was performed for detection of degenerative neuron.We observed iron retention by Perl's staining,activation of microglia by OX-6 staining and activation of NF-κB by phosphor-P65 subunit staining.Ferritin expression and its distribution on microglia were also investigated.Chelation of iron with deferoxamine was carried out in ICH model to evaluate the role of intracerebral iron accumulation on delayed brain atrophy and neurological functions.Also,the influence of minocycline on delayed brain injury was investigated.Part 2:Cultured microglias were treated with ferrous chloride and the activation of microglia and NF-κB was observed.Then we investigated the possible mechanism of neurotoxicity of iron by direct administration of ferrous iron to neurons or the conditioned medium composed of supernatant from microglia pre-treated with ferrous iron.Minocycline was used and its role on inhibition of microglial activation was observed.
Results:
Persistent iron retention and increase in immunity of ferritin were confirmed in ICH.Co-localization of ferritin and OX-42 suggested the expression of ferritin in microglia during chronic stage.As compared with 2 weeks after hemorrhage,a significant brain atrophy occured 6 weeks later.FJC positive cells,indicative of degenerative neurons,could be found in the fight basal ganglia at 2weeks.FJC positive cells were also found in CA1 area of hippocampus in ferrous chloride model.Treatment with deferoxamine could prevent the delayed atrophy.Persistent activation of microglia and NF-κB was observed after blood infusion or ferrous chloride administration as revealed by OX-6 and phosphor-P65 staining.Minocycline could inhibit the delayed brain atrophy.Ferrous iron was capable of inducing the activation of cultured microglia. Direct use of ferrous iron couldn't cause increase of LDH activity of cultured neurons, while the administration of conditioned medium induced injury of neurons as shown by elevation of LDH activity and dead/live ratio,both of which were reversed by minocycline.Treatment of microglia with ferrous iron for 30min induced the activation of NF-κB,which could also be inhibited by minocycline.
Conclusion:
1) Delayed brain atrophy and neuron loss occur during chronic stage in rat ICH.
2) In vitro,ferrous iron can induce activation of microglia directly which can in turn exert injury to neurons.
3) Iron retention is involved in the delayed brain injury.The iron may activate microglia which therefore results in injury of the surrounding neurons.NF-κB may participate in the process.
脑出血后血红蛋白降解释放的铁离子在急性期过后仍长期滞留于脑内。本研究拟观察脑出血后潴留于脑内的铁离子是否对脑组织产生迟发性损伤,并对其机制进行探索。
研究方法:
本研究分两部分。第一部分:通过大鼠自体血基底节模型和大鼠海马氯化亚铁注射模型,观察是否存在迟发性脑萎缩并进行FJC染色检测建模后2周时是否仍存在神经元变性。同时,在不同时间点应用Perl's染色观察铁离子脑内潴留情况,应用OX-6染色观察小胶质细胞激活情况,运用磷酸化P65染色观察NF-κB活化情况,运用铁蛋白/OX-42复染观察脑出血后铁蛋白在小胶质细胞中的表达情况。并观察铁离子螯合和米诺环素治疗对迟发性脑萎缩和神经功能的影响。第二部分:进行小胶质细胞和神经元培养。通过OX-6染色和磷酸化P65染色分别观察Fe~(2+)对小胶质细胞的激活作用和对小胶质细胞NF-κB活化的影响。通过Fe~(2+)直接处理神经元和Fe~(2+)处理小胶质细胞后所得上清再处理神经元观察Fe~(2+)对神经元的作用途径,明确小胶质细胞在其中的作用,并给予米诺环素进行干预治疗。
结果:
大鼠脑出血模型中12周仍存在铁离子潴留和出血侧铁蛋白染色增强,复染提示脑出血后4周后铁蛋白轻/重链主要表达于小胶质细胞。脑出血后2周时,出血侧基底节未见明显萎缩,在4周时萎缩出现,到8周时则更显著。FJC染色提示2周时,血肿侧仍有变性神经元存在。在海马FeCl_2注射模型中也能在2周时检测到变性神经元。铁离子螯合治疗可以有效减轻脑出血后的迟发性脑萎缩。小胶质细胞激活和NF-κB的活化现象在脑出血模型和海马FeCl_2模型中都存在并至少持续至建模后2周。米诺环素可以减轻脑出血后的迟发性脑萎缩。Fe~(2+)能直接激活培养小胶质细胞。Fe~(2+)直接作用于培养神经元,不能引起其LDH水平的增高,而Fe~(2+)处理后的小胶质细胞进一步孵育产生的上清对神经元具有损伤作用,应用米诺环素则能有效逆转这种损伤,米诺环素还能抑制小胶质细胞激活和NF-κB的活化。
结论:
1)大鼠脑出血模型中存在迟发性脑损伤。2)Fe~(2+)可以通过激活小胶质细胞进而引起神经细胞的死亡。3)脑出血后迟发性脑损伤与铁离子长期潴留于脑内有关。长期潴留于脑内的铁离子可能通过小胶质细胞激活引起神经元的迟发性变性死亡。NF-κB活化可能参与了这一过程。研究不仅揭示脑出血后存在的迟发性损伤这一病理现象并对其机制进行了探讨,同时也为今后临床治疗提供了新的思路。
Purpose:
Persistent iron retention is observed after intracerebral hemorrhage(ICH),while weather it makes delayed injury to brain remains unknown.The present study focuses on the possible effects and mechanism of accumulated iron on brain tissues during chronic stage of ICH.
Methods:
The study was including 2 parts.Part 1:A ICH model was set up by infusion of 100μl autologous blood into right basal ganglia of SD rat and a ferrous iron model was set up by insertion of 30μl ferrous chloride of 10mM into right hippocampus of rat seperately.Delayed brain atrophy was assessed and Fluoro-Jade C(FJC) staining at 2weeks after ICH was performed for detection of degenerative neuron.We observed iron retention by Perl's staining,activation of microglia by OX-6 staining and activation of NF-κB by phosphor-P65 subunit staining.Ferritin expression and its distribution on microglia were also investigated.Chelation of iron with deferoxamine was carried out in ICH model to evaluate the role of intracerebral iron accumulation on delayed brain atrophy and neurological functions.Also,the influence of minocycline on delayed brain injury was investigated.Part 2:Cultured microglias were treated with ferrous chloride and the activation of microglia and NF-κB was observed.Then we investigated the possible mechanism of neurotoxicity of iron by direct administration of ferrous iron to neurons or the conditioned medium composed of supernatant from microglia pre-treated with ferrous iron.Minocycline was used and its role on inhibition of microglial activation was observed.
Results:
Persistent iron retention and increase in immunity of ferritin were confirmed in ICH.Co-localization of ferritin and OX-42 suggested the expression of ferritin in microglia during chronic stage.As compared with 2 weeks after hemorrhage,a significant brain atrophy occured 6 weeks later.FJC positive cells,indicative of degenerative neurons,could be found in the fight basal ganglia at 2weeks.FJC positive cells were also found in CA1 area of hippocampus in ferrous chloride model.Treatment with deferoxamine could prevent the delayed atrophy.Persistent activation of microglia and NF-κB was observed after blood infusion or ferrous chloride administration as revealed by OX-6 and phosphor-P65 staining.Minocycline could inhibit the delayed brain atrophy.Ferrous iron was capable of inducing the activation of cultured microglia. Direct use of ferrous iron couldn't cause increase of LDH activity of cultured neurons, while the administration of conditioned medium induced injury of neurons as shown by elevation of LDH activity and dead/live ratio,both of which were reversed by minocycline.Treatment of microglia with ferrous iron for 30min induced the activation of NF-κB,which could also be inhibited by minocycline.
Conclusion:
1) Delayed brain atrophy and neuron loss occur during chronic stage in rat ICH.
2) In vitro,ferrous iron can induce activation of microglia directly which can in turn exert injury to neurons.
3) Iron retention is involved in the delayed brain injury.The iron may activate microglia which therefore results in injury of the surrounding neurons.NF-κB may participate in the process.
引文
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