NGF/TrkA对大鼠海马TRPM7的调节作用
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摘要
第一部分NGF对脑缺血大鼠海马TRPM7表达水平的影响
最近的研究表明transient receptor potential melastatin 7 (TRPM7)通道的活动和缺氧神经元的死亡密切相关,但是TRPM7通道的表达在缺血缺氧损伤过程中如何变化或如何被调节尚未见报导。本研究通过建立脑缺血的在体和离体模型从整体和细胞水平探讨神经生长因子(nerve growth factor NGF)对海马TRPM7表达水平的影响。实验选用SD大鼠,以大脑中动脉栓塞(middle cerebral artery occlusion MCAO)法制备短暂局灶性脑缺血再灌注模型,对原代培养的海马神经元作氧糖剥夺(oxygen-glucose deprivation OGD)处理建立神经元缺血的离体研究模型,利用RT-PCR和Western blot技术检测不同时段海马TRPM7的表达水平和NGF对TRPM7表达水平的影响,利用免疫细胞化学技术结合激光共聚焦观察定位TRPM7蛋白和TrkA受体在海马神经元的分布。
在体研究显示:
1)以MCAO法制备短暂局灶性脑缺血再灌注动物模型,大鼠缺血侧海马组织TRPM7 mRNA水平显著升高,与假手术组和正常组相比,差异有显著性(P<0.05);并且在缺血再灌注后15~20小时TRPM7 mRNA表达升高到稳定水平;
2)对缺血再灌注大鼠侧脑室注射NGF后,缺血侧海马组织TRPM7异常高表达被抑制,其mRNA和蛋白水平与假手术组相比无显著差异(P>0.05),与缺血再灌注组相比有显著性差异(P<0.05),此效应可被TrkA的拮抗剂K252a阻断。
离体研究显示:
1) TrkA和TRPM7共存于同一海马神经元的胞体上。
2)OGD可诱导LDH大量释放及海马神经元大量死亡,与正常对照组相比,差异非常显著(P<0.01)。NGF处理组与未经NGF处理组相比,细胞外LDH浓度和神经元的死亡率显著下降(P<0.05),存活率显著升高(P<0.05);这种保护作用在NGF+K252a一组的细胞中却不明显(P>0.05)。
3)OGD可诱导海马神经元TRPM7 mRNA和蛋白水平的异常高表达,与正常组相比,两者间有显著升高(P<0.05);NGF处理可抑制OGD神经元TRPM7 mRNA和蛋白的异常高表达,与未经NGF处理组比较,两者之间有显著性差异(P<0.05),此效应可被TrkA受体拮抗剂K252a拮抗。
4)进一步用Wortmannin抑制phosphatidylinsitol-3 kinase (PI-3K)、U73122抑制phospholipase C (PLC)和Sos inhibitory peptide抑制sos和ras的结合,以观察TrkA下游三条通路对NGF效应的影响。发现:与NGF组相比,NGF和Wortmannin共孵育完全逆转了NGF对TRPM7表达的抑制作用(P<0.05);但是,用U73122或Sos inhibitory peptide均无此效应。这些结果显示PI-3K通路介导了NGF对缺氧缺糖损伤诱导的TRPM7高表达的下调作用。
以上结果表明缺血缺氧损伤可诱导海马TRPM7的高表达,NGF可通过TrkA来抑制TRPM7的高表达,这种抑制作用是通过TrkA下游的PI-3K信号转导通路介导的。基于TrkA和TRPM7都表达于富含NGF的海马组织中,这些结果为进一步探索NGF和TRPM7在缺血缺氧的海马神经元中所起的作用提供了有用的线索。
第二部分NGF对大鼠海马CA1区神经元TRPM7电流的调节
虽然TRPM7通道广泛表达于中枢神经系统,但是对于该通道的功能和调节机制人们仍知之甚少。本研究运用全细胞膜片钳技术探讨NGF对海马CA1神经元TRPM7通道电流的作用。我们首先在急性分离的大鼠(出生后10天)海马CA1区神经元上记录到具有外向整流特征的典型的“TRPM7样电流”;进而发现NGF对这一电流的外向成分有显著的可逆的抑制作用。这种抑制效应具有浓度和时间依赖性。K252a可阻断NGF对“TRPM7样电流”的抑制作用;进一步用TrkA下游效应分子磷脂酶C的拮抗剂U73122也可逆转这种抑制效应。这些结果表明NGF可通过TrkA之PLC信号转导通路抑制海马神经元TRPM7通道的功能。
第三部分电针通过TrkA通路对脑缺血大鼠海马TRPM7表达的影响
虽然临床资料表明电针治疗对中风患者有一定疗效,但是人们对此疗效产生的具体机制知之甚少。我们的前期工作表明电针可通过上调缺血脑组织的TrkA受体介导神经元保护作用。本实验通过制备大鼠大脑中动脉栓塞模型,发现电针治疗可减少缺血海马组织TRPM7的高表达。通过使用TrkA信号转导通路的特异的拮抗剂,我们发现PI-3K通路可能介导了电针对缺血海马的TRPM7表达的下调作用。基于TRPM7已被发现在缺氧神经元死亡过程中发挥关键作用,这些结果为临床运用电针治疗中风的机理提供了实验依据。
Part 1 Effect of nerve growth factor on TRPM7 expression in ischemic rat hipppocampus
Although the activity of transient receptor potential melastatin 7 (TRPM7) channels correlates with anoxic neuronal death in recent reports; the change or regulation of TRPM7 expression in response to ischemic insult has not been documented. Using in vivo (middle cerebral artery occlusion MCAO) and in vitro (oxygen-glucose deprivation OGD) models of cerebral ischemia, we explored the effect of nerve growth factor (NGF) on the expression of TRPM7 in rat hippocampus by means of RT-PCR and Western blot analyses. We also observed the staining pattern of TRPM7 and TrkA in hippocampal neurons by means of confocal laser scanning microscopy.
The results obtained from in vivo research:
(1) Compared with Sham and Normal groups TRPM7 mRNA expression in ipsilateral hippocampi of MCAO rats significantly increased (P<0.05) and became stable during 15~20 h after reperfusion.
(2) Compared with Ischemia group, intracerebroventricular injection of NGF significantly reduced mRNA and protein expression of TRPM7 at 20 h after reperfusion (P<0.05), which could be abolished by co-application of TrkA inhibitor K252a.
The results obtained from in vitro research:
(1) The co-localization of TRPM7 and TrkA were found in cell bodies of the same hippocampal neurons.
(2) OGD induced significant increase of LDH release and neuronal death, compared with control group (P<0.01). Pre-incubation of NGF markedly reduced extracellular LDH concentration and neuronal death, compared with OGD-treated cultures without NGF treatment (P<0.05); co-application with K252a fully abolished this protective effect of NGF (P>0.05).
(3) Compared with control group, TRPM7 expression in hippocampal cultures was significantly increased at 20 h after OGD treatment (P<0.05). In contrast, pre-incubation of NGF markedly reduced TRPM7 expression, compared with OGD-treated cultures without NGF treatment (P<0.05); this inhibitory effect could be abolished by K252a.
(4) When specific inhibitors were further introduced to selectively block phosphatidylinsitol-3 kinase (PI-3K), phospholipase C (PLC) or ras pathways, only PI-3K inhibitor Wortmannin abolished NGF effect on TRPM7 expression of OGD-treated cultures.
All above results indicate that cerebral ischemia may induce highly expressed TRPM7 in hippocampus and TrkA, when activated by NGF, may prevent high expression of TRPM7 through PI-3K signal pathway. In light of the abundance of NGF in hippocampus that express both TrkA and TRPM7, these findings offers some clues for further investigation of potential roles of TRPM7 and NGF in hippocampal neurons during cerebral ischemia.
Part 2 Regulation of a TRPM7-like current by NGF in rat CA1 hippocampal neurons
TRPM7 channels are widely expressed in the nervous system; however their function and regulation are largely unknown. This study aimed to explore whether the current mediated by TRPM7-like channels in rat CA1 hippocampal neurons could be modulated by NGF. Using whole-cell patch clamp recording techniques, we identified an outward-rectifying TRPM7-like current in CA1 hippocampal neurons freshly isolated from postnatal (10-day-old) rats. Tthe outward component of this current was reversibly reduced by NGF in dose- and time- dependent manners; and this effect was blocked by K252a. In addition, when U73122 was further introduced to inhibit the TrkA downstream effector phopholipase C in the presence of NGF, the reduction of the current was also abolished. These results suggest that NGF, by activing TrkA may regulate the function of TRPM7-like channels in hippocampal neurons via PLC pathway.
Part 3 Effect of electroacupuncture on TRPM7 expression via TrkA in ischemic rat hipppocampus
Clinically, electroacupuncture (EA) has been shown to produce beneficial effect on stroke patients. However, the detailed mechanism underlying the beneficial effects of EA on stroke remains poorly understood. Our previous studies have shown that EA may up-regulate TrkA in brain tissues during cerebral ischemia and mediate neuroprotective effects. In this experiment, we found that EA treatment reduced high expression of TRPM7 in ischemic hippocampal tissues in the rat mode of middle cerebral artery occlusion. Using protein kinase inhibitors of specific TrkA signaling pathways, we found that this reduction appears to be mediated through PI-3K pathway. In view that TRPM7 has recently been found to play a key role in the death of anoxic neurons, our results may provide experimental evidence for the clinical application of EA treatment for stroke patients.
最近的研究表明transient receptor potential melastatin 7 (TRPM7)通道的活动和缺氧神经元的死亡密切相关,但是TRPM7通道的表达在缺血缺氧损伤过程中如何变化或如何被调节尚未见报导。本研究通过建立脑缺血的在体和离体模型从整体和细胞水平探讨神经生长因子(nerve growth factor NGF)对海马TRPM7表达水平的影响。实验选用SD大鼠,以大脑中动脉栓塞(middle cerebral artery occlusion MCAO)法制备短暂局灶性脑缺血再灌注模型,对原代培养的海马神经元作氧糖剥夺(oxygen-glucose deprivation OGD)处理建立神经元缺血的离体研究模型,利用RT-PCR和Western blot技术检测不同时段海马TRPM7的表达水平和NGF对TRPM7表达水平的影响,利用免疫细胞化学技术结合激光共聚焦观察定位TRPM7蛋白和TrkA受体在海马神经元的分布。
在体研究显示:
1)以MCAO法制备短暂局灶性脑缺血再灌注动物模型,大鼠缺血侧海马组织TRPM7 mRNA水平显著升高,与假手术组和正常组相比,差异有显著性(P<0.05);并且在缺血再灌注后15~20小时TRPM7 mRNA表达升高到稳定水平;
2)对缺血再灌注大鼠侧脑室注射NGF后,缺血侧海马组织TRPM7异常高表达被抑制,其mRNA和蛋白水平与假手术组相比无显著差异(P>0.05),与缺血再灌注组相比有显著性差异(P<0.05),此效应可被TrkA的拮抗剂K252a阻断。
离体研究显示:
1) TrkA和TRPM7共存于同一海马神经元的胞体上。
2)OGD可诱导LDH大量释放及海马神经元大量死亡,与正常对照组相比,差异非常显著(P<0.01)。NGF处理组与未经NGF处理组相比,细胞外LDH浓度和神经元的死亡率显著下降(P<0.05),存活率显著升高(P<0.05);这种保护作用在NGF+K252a一组的细胞中却不明显(P>0.05)。
3)OGD可诱导海马神经元TRPM7 mRNA和蛋白水平的异常高表达,与正常组相比,两者间有显著升高(P<0.05);NGF处理可抑制OGD神经元TRPM7 mRNA和蛋白的异常高表达,与未经NGF处理组比较,两者之间有显著性差异(P<0.05),此效应可被TrkA受体拮抗剂K252a拮抗。
4)进一步用Wortmannin抑制phosphatidylinsitol-3 kinase (PI-3K)、U73122抑制phospholipase C (PLC)和Sos inhibitory peptide抑制sos和ras的结合,以观察TrkA下游三条通路对NGF效应的影响。发现:与NGF组相比,NGF和Wortmannin共孵育完全逆转了NGF对TRPM7表达的抑制作用(P<0.05);但是,用U73122或Sos inhibitory peptide均无此效应。这些结果显示PI-3K通路介导了NGF对缺氧缺糖损伤诱导的TRPM7高表达的下调作用。
以上结果表明缺血缺氧损伤可诱导海马TRPM7的高表达,NGF可通过TrkA来抑制TRPM7的高表达,这种抑制作用是通过TrkA下游的PI-3K信号转导通路介导的。基于TrkA和TRPM7都表达于富含NGF的海马组织中,这些结果为进一步探索NGF和TRPM7在缺血缺氧的海马神经元中所起的作用提供了有用的线索。
第二部分NGF对大鼠海马CA1区神经元TRPM7电流的调节
虽然TRPM7通道广泛表达于中枢神经系统,但是对于该通道的功能和调节机制人们仍知之甚少。本研究运用全细胞膜片钳技术探讨NGF对海马CA1神经元TRPM7通道电流的作用。我们首先在急性分离的大鼠(出生后10天)海马CA1区神经元上记录到具有外向整流特征的典型的“TRPM7样电流”;进而发现NGF对这一电流的外向成分有显著的可逆的抑制作用。这种抑制效应具有浓度和时间依赖性。K252a可阻断NGF对“TRPM7样电流”的抑制作用;进一步用TrkA下游效应分子磷脂酶C的拮抗剂U73122也可逆转这种抑制效应。这些结果表明NGF可通过TrkA之PLC信号转导通路抑制海马神经元TRPM7通道的功能。
第三部分电针通过TrkA通路对脑缺血大鼠海马TRPM7表达的影响
虽然临床资料表明电针治疗对中风患者有一定疗效,但是人们对此疗效产生的具体机制知之甚少。我们的前期工作表明电针可通过上调缺血脑组织的TrkA受体介导神经元保护作用。本实验通过制备大鼠大脑中动脉栓塞模型,发现电针治疗可减少缺血海马组织TRPM7的高表达。通过使用TrkA信号转导通路的特异的拮抗剂,我们发现PI-3K通路可能介导了电针对缺血海马的TRPM7表达的下调作用。基于TRPM7已被发现在缺氧神经元死亡过程中发挥关键作用,这些结果为临床运用电针治疗中风的机理提供了实验依据。
Part 1 Effect of nerve growth factor on TRPM7 expression in ischemic rat hipppocampus
Although the activity of transient receptor potential melastatin 7 (TRPM7) channels correlates with anoxic neuronal death in recent reports; the change or regulation of TRPM7 expression in response to ischemic insult has not been documented. Using in vivo (middle cerebral artery occlusion MCAO) and in vitro (oxygen-glucose deprivation OGD) models of cerebral ischemia, we explored the effect of nerve growth factor (NGF) on the expression of TRPM7 in rat hippocampus by means of RT-PCR and Western blot analyses. We also observed the staining pattern of TRPM7 and TrkA in hippocampal neurons by means of confocal laser scanning microscopy.
The results obtained from in vivo research:
(1) Compared with Sham and Normal groups TRPM7 mRNA expression in ipsilateral hippocampi of MCAO rats significantly increased (P<0.05) and became stable during 15~20 h after reperfusion.
(2) Compared with Ischemia group, intracerebroventricular injection of NGF significantly reduced mRNA and protein expression of TRPM7 at 20 h after reperfusion (P<0.05), which could be abolished by co-application of TrkA inhibitor K252a.
The results obtained from in vitro research:
(1) The co-localization of TRPM7 and TrkA were found in cell bodies of the same hippocampal neurons.
(2) OGD induced significant increase of LDH release and neuronal death, compared with control group (P<0.01). Pre-incubation of NGF markedly reduced extracellular LDH concentration and neuronal death, compared with OGD-treated cultures without NGF treatment (P<0.05); co-application with K252a fully abolished this protective effect of NGF (P>0.05).
(3) Compared with control group, TRPM7 expression in hippocampal cultures was significantly increased at 20 h after OGD treatment (P<0.05). In contrast, pre-incubation of NGF markedly reduced TRPM7 expression, compared with OGD-treated cultures without NGF treatment (P<0.05); this inhibitory effect could be abolished by K252a.
(4) When specific inhibitors were further introduced to selectively block phosphatidylinsitol-3 kinase (PI-3K), phospholipase C (PLC) or ras pathways, only PI-3K inhibitor Wortmannin abolished NGF effect on TRPM7 expression of OGD-treated cultures.
All above results indicate that cerebral ischemia may induce highly expressed TRPM7 in hippocampus and TrkA, when activated by NGF, may prevent high expression of TRPM7 through PI-3K signal pathway. In light of the abundance of NGF in hippocampus that express both TrkA and TRPM7, these findings offers some clues for further investigation of potential roles of TRPM7 and NGF in hippocampal neurons during cerebral ischemia.
Part 2 Regulation of a TRPM7-like current by NGF in rat CA1 hippocampal neurons
TRPM7 channels are widely expressed in the nervous system; however their function and regulation are largely unknown. This study aimed to explore whether the current mediated by TRPM7-like channels in rat CA1 hippocampal neurons could be modulated by NGF. Using whole-cell patch clamp recording techniques, we identified an outward-rectifying TRPM7-like current in CA1 hippocampal neurons freshly isolated from postnatal (10-day-old) rats. Tthe outward component of this current was reversibly reduced by NGF in dose- and time- dependent manners; and this effect was blocked by K252a. In addition, when U73122 was further introduced to inhibit the TrkA downstream effector phopholipase C in the presence of NGF, the reduction of the current was also abolished. These results suggest that NGF, by activing TrkA may regulate the function of TRPM7-like channels in hippocampal neurons via PLC pathway.
Part 3 Effect of electroacupuncture on TRPM7 expression via TrkA in ischemic rat hipppocampus
Clinically, electroacupuncture (EA) has been shown to produce beneficial effect on stroke patients. However, the detailed mechanism underlying the beneficial effects of EA on stroke remains poorly understood. Our previous studies have shown that EA may up-regulate TrkA in brain tissues during cerebral ischemia and mediate neuroprotective effects. In this experiment, we found that EA treatment reduced high expression of TRPM7 in ischemic hippocampal tissues in the rat mode of middle cerebral artery occlusion. Using protein kinase inhibitors of specific TrkA signaling pathways, we found that this reduction appears to be mediated through PI-3K pathway. In view that TRPM7 has recently been found to play a key role in the death of anoxic neurons, our results may provide experimental evidence for the clinical application of EA treatment for stroke patients.
引文
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