神经激肽NK1、NK3对基底前脑神经元兴奋性毒性损伤的不同调节作用
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摘要
老年性痴呆(Alzheimer’s disease,AD)是常见的中枢神经变性疾病,其确切的病因不清。研究发现,AD患者基底前脑胆碱能神经元死亡明显,兴奋性毒性损伤是导致神经元损伤与AD发病的重要因素。神经激肽是包括P物质(Neurokinin-1,NK1)、神经激肽A(Neurokinin-2,NK2)、神经激肽B(Neurokinin-3,NK3)的速激肽家族,其生物学效应由相应的NK1、NK2和NK3受体来介导。研究表明,神经激肽-神经激肽受体在基底前脑胆碱能神经元分布丰富,但其功能尚不清楚。我们课题组以往的实验研究发现,神经激肽在调节基底核纹状体和黑质神经元兴奋性毒性损伤中具有重要作用。进一步探讨神经激肽对基底前脑胆碱能神经元兴奋性毒性的调节作用,对于揭示AD的病理发生机制和探索其治疗策略,具有重要意义。
因此,本研究采用海人藻酸(kainic acid,KA)诱导兴奋性毒性小鼠模型、分别给予NK1、NK3受体特异性激动剂(septide、senktide),NK3受体拮抗剂(SB218795)干预方法、Fluoro-Jade B染色、免疫荧光双标记与激光共聚焦显微镜等技术,观察分析了神经激肽NK1、NK3对基底前脑神经元兴奋性毒性损伤和死亡的调节作用及其可能机制。主要结果如下:
1.神经激肽NK1、NK3受体与离子型谷氨酸受体共存于基底前脑神经元。细胞计数结果表明,约57-95%NK1受体阳性神经元表达AMPA受体亚基GluR1、2、3、4,约14%-77%NK3受体阳性神经元表达AMPA受体亚基GluR1、2、3和NMDA受体亚基NR1。
2.神经激肽NK1、NK3对KA注射诱导基底前脑神经元兴奋性毒性损伤产生不同的调节作用。NK1受体激动剂具有神经保护作用,而NK3受体激动剂具有兴奋性毒性的协同效应。结果表明:与KA注射组相比,NK1受体激动剂septide干预组的Fluoro-Jade B阳性神经元数量减少,ChAT阳性神经元存活率增加(28%)。而NK3受体激动剂senktide处理组Fluoro-Jade B阳性神经元数目增多,ChAT阳性神经元存活率减少(22%)。NK3受体拮抗剂SB218795处理组Fluoro-Jade B阳性神经元降低,ChAT阳性神经元存活率增加(18%)。
3.应用不同的双标记方法分析,几乎全部(约100%)基底前脑死亡细胞为神经元,Fluoro-Jade B染色神经元数量与磷酸化NMDA受体上调和D-serine阳性神经元具有密切关系(正相关)。初步结论:
1.神经激肽NK1、NK3受体和谷氨酸AMPA、NMDA受体共存于基底前脑神经元,提供了神经激肽调节兴奋性信号的受体学基础。
2.神经激肽NK1、NK3对基底前脑神经元兴奋性毒性损伤具有不同的调节作用,其中NK1具有神经保护作用,而NK3则具有兴奋性神经毒性的协同效应。
本研究提供了神经激肽NK1、NK3调节基底前脑神经元兴奋性毒性损伤和死亡的新证据,对于揭示AD的病理发生机制和进一步探索AD治疗的药物干预靶位,均具有重要意义。
Alzheimer’s disease (AD) is one common and severe neurodegenerative disease in human beings, but so far the pathogenesis of AD has been ambiguous. Previous studies have shown that massive loss of cholinergic neurons in the basal forebrain are obvious in the AD pathogenesis, and the glutamate-driving excitotoxicity consititutes one of main reasons resulting in the death of these neurons. Intervention ways of excitotoxicity has thus raised much research interests, which may promte to set up new therapy against AD.
Mammalian neurokinins(NKs)are a family of tachykinin peptides that include substance P (neurokinin-1,NK1), neurokinin A (neurokinin-2, NK2) and neurokinin B (neurokinin-3, NK3). Their biological functions are mediated by three distinct neurokinin receptors, namely NK1 receptor, NK2 receptor and NK3 receptor. Neurokinin peptides and neurokinin receptors are abundantly distributed in the basal forebrain regions, but their function is unclear. In the previous observations we have found that neurokinins are involved in regulating excitotoxicity in the striatal and substantia nigra neurons. Further studies should be devoted to elucidate whether neurokinins are involved in modulating exicitotoxicity or exicitotoxic death of basal forebrain neurons.
Therefore, the intervention roles of neurokinins NK1, NK3 in regulation of excitotoxicity of cholinergic neurons in the basal forebrain and possible interaction substrate were studied by using animal models induced by kainic acid (KA) leison, administration of neuronkinin receptor specific agonists and antagonist, Fluoro-Jade B (FJB) staining for visualizing neuronal degeneration, choline acetyltransferase (ChAT)-immunohistochemistry, double immuno- fluorescence and laser scanning confocal microscopy.
Firstly, colocalization of AMPA and NMDA glutamate receptor subunits were found in both NK1R-containing neurons and NK3R-containing neurons in the basal forebrain of mice. Semiquantitative analysis revealed that majority (57-95%) of NK1R-positive neurons express AMPA receptor subunits GluR1-4, and NK3R-positive neurons (14%-77%) express AMPA receptor subunits GluR1-3 and NMDA receptor subunit 1.
Secondly, the differential interventions roles of neurokinins NK1 and NK3 were found in regulating KA-induced excitotoxic neuronal injuries of basal forebrain in animal models. It revealed that NK1 exhibited neuronal protection, while the NK3 potentated neuronal excitotoxicity. In compared with single KA injection group, pretreatment with NK1 receptor agonist septide decreased FJB-positive neurons and increased ChAT-postive ones, while pretreatment with NK3 receptor agonist senktide increased FJB-positive neurons and decreased ChAT-positive ones. Experiment with NK3 receptor antagonist SB218795 confirmed effect of NK3 on excitotoxicity.
Thirdly, double labeling experiments were further applied to identify cell types of FJB stained cells and possible involvement of D-serine or phosphorylation of NMDA receptor 1 (pNMDAR1) in the death of basal forebrain neurons. It revealed that nearly all (100%) of FJB-positive cells were neurons, and they overlapped with that of pNMDAR1 or D-serine-positive neurons in the injured basal forebrain.
This study presents evidence on neuronal colocalization of NK1/NK3 and AMPA/NMDA receptors, which provided substrate for functional interaction between neurokinins and glutamate signals in the basal forebrain. More interestingly, differential intervention roles of neurokinins NK1 and NK3 have been found in regulation of excitotoxic injuries of neurons in the basal forebrain, in which NK1 has neuroprotection effect, while NK3 exhibits synergistic effect on neurotoxicity in the basal forebrain. This study suggests that neurokinin peptides may implicate in pathogenesis of neurodegenerative diseases and neurokinin receptors may act as potential intervention targets in the neuroprotection treatment of AD in human beings.
因此,本研究采用海人藻酸(kainic acid,KA)诱导兴奋性毒性小鼠模型、分别给予NK1、NK3受体特异性激动剂(septide、senktide),NK3受体拮抗剂(SB218795)干预方法、Fluoro-Jade B染色、免疫荧光双标记与激光共聚焦显微镜等技术,观察分析了神经激肽NK1、NK3对基底前脑神经元兴奋性毒性损伤和死亡的调节作用及其可能机制。主要结果如下:
1.神经激肽NK1、NK3受体与离子型谷氨酸受体共存于基底前脑神经元。细胞计数结果表明,约57-95%NK1受体阳性神经元表达AMPA受体亚基GluR1、2、3、4,约14%-77%NK3受体阳性神经元表达AMPA受体亚基GluR1、2、3和NMDA受体亚基NR1。
2.神经激肽NK1、NK3对KA注射诱导基底前脑神经元兴奋性毒性损伤产生不同的调节作用。NK1受体激动剂具有神经保护作用,而NK3受体激动剂具有兴奋性毒性的协同效应。结果表明:与KA注射组相比,NK1受体激动剂septide干预组的Fluoro-Jade B阳性神经元数量减少,ChAT阳性神经元存活率增加(28%)。而NK3受体激动剂senktide处理组Fluoro-Jade B阳性神经元数目增多,ChAT阳性神经元存活率减少(22%)。NK3受体拮抗剂SB218795处理组Fluoro-Jade B阳性神经元降低,ChAT阳性神经元存活率增加(18%)。
3.应用不同的双标记方法分析,几乎全部(约100%)基底前脑死亡细胞为神经元,Fluoro-Jade B染色神经元数量与磷酸化NMDA受体上调和D-serine阳性神经元具有密切关系(正相关)。初步结论:
1.神经激肽NK1、NK3受体和谷氨酸AMPA、NMDA受体共存于基底前脑神经元,提供了神经激肽调节兴奋性信号的受体学基础。
2.神经激肽NK1、NK3对基底前脑神经元兴奋性毒性损伤具有不同的调节作用,其中NK1具有神经保护作用,而NK3则具有兴奋性神经毒性的协同效应。
本研究提供了神经激肽NK1、NK3调节基底前脑神经元兴奋性毒性损伤和死亡的新证据,对于揭示AD的病理发生机制和进一步探索AD治疗的药物干预靶位,均具有重要意义。
Alzheimer’s disease (AD) is one common and severe neurodegenerative disease in human beings, but so far the pathogenesis of AD has been ambiguous. Previous studies have shown that massive loss of cholinergic neurons in the basal forebrain are obvious in the AD pathogenesis, and the glutamate-driving excitotoxicity consititutes one of main reasons resulting in the death of these neurons. Intervention ways of excitotoxicity has thus raised much research interests, which may promte to set up new therapy against AD.
Mammalian neurokinins(NKs)are a family of tachykinin peptides that include substance P (neurokinin-1,NK1), neurokinin A (neurokinin-2, NK2) and neurokinin B (neurokinin-3, NK3). Their biological functions are mediated by three distinct neurokinin receptors, namely NK1 receptor, NK2 receptor and NK3 receptor. Neurokinin peptides and neurokinin receptors are abundantly distributed in the basal forebrain regions, but their function is unclear. In the previous observations we have found that neurokinins are involved in regulating excitotoxicity in the striatal and substantia nigra neurons. Further studies should be devoted to elucidate whether neurokinins are involved in modulating exicitotoxicity or exicitotoxic death of basal forebrain neurons.
Therefore, the intervention roles of neurokinins NK1, NK3 in regulation of excitotoxicity of cholinergic neurons in the basal forebrain and possible interaction substrate were studied by using animal models induced by kainic acid (KA) leison, administration of neuronkinin receptor specific agonists and antagonist, Fluoro-Jade B (FJB) staining for visualizing neuronal degeneration, choline acetyltransferase (ChAT)-immunohistochemistry, double immuno- fluorescence and laser scanning confocal microscopy.
Firstly, colocalization of AMPA and NMDA glutamate receptor subunits were found in both NK1R-containing neurons and NK3R-containing neurons in the basal forebrain of mice. Semiquantitative analysis revealed that majority (57-95%) of NK1R-positive neurons express AMPA receptor subunits GluR1-4, and NK3R-positive neurons (14%-77%) express AMPA receptor subunits GluR1-3 and NMDA receptor subunit 1.
Secondly, the differential interventions roles of neurokinins NK1 and NK3 were found in regulating KA-induced excitotoxic neuronal injuries of basal forebrain in animal models. It revealed that NK1 exhibited neuronal protection, while the NK3 potentated neuronal excitotoxicity. In compared with single KA injection group, pretreatment with NK1 receptor agonist septide decreased FJB-positive neurons and increased ChAT-postive ones, while pretreatment with NK3 receptor agonist senktide increased FJB-positive neurons and decreased ChAT-positive ones. Experiment with NK3 receptor antagonist SB218795 confirmed effect of NK3 on excitotoxicity.
Thirdly, double labeling experiments were further applied to identify cell types of FJB stained cells and possible involvement of D-serine or phosphorylation of NMDA receptor 1 (pNMDAR1) in the death of basal forebrain neurons. It revealed that nearly all (100%) of FJB-positive cells were neurons, and they overlapped with that of pNMDAR1 or D-serine-positive neurons in the injured basal forebrain.
This study presents evidence on neuronal colocalization of NK1/NK3 and AMPA/NMDA receptors, which provided substrate for functional interaction between neurokinins and glutamate signals in the basal forebrain. More interestingly, differential intervention roles of neurokinins NK1 and NK3 have been found in regulation of excitotoxic injuries of neurons in the basal forebrain, in which NK1 has neuroprotection effect, while NK3 exhibits synergistic effect on neurotoxicity in the basal forebrain. This study suggests that neurokinin peptides may implicate in pathogenesis of neurodegenerative diseases and neurokinin receptors may act as potential intervention targets in the neuroprotection treatment of AD in human beings.
引文
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