应用Fluoro-Jade C方法研究神经激肽NK3对黑质多巴胺神经元兴奋性毒性损伤的干预作用
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摘要
帕金森病(Parkinson’s disease, PD)是一种常见的中枢神经变性疾病,患者出现静止性震颤、运动迟缓、僵硬、步态异常和姿势不稳等严重的运动症状。PD的典型病理变化为大量黑质多巴胺神经元变性死亡,现行的PD治疗方法不能阻止黑质神经元进行性死亡和PD病发生。以往研究表明在引起黑质多巴胺神经元死亡和PD发生的多种因素中,谷氨酸兴奋性毒性可能是重要原因之一。因此,探索阻止谷氨酸兴奋性毒性损伤和保护黑质多巴胺神经元的新手段,对于完善PD治疗十分必要。
神经激肽(Neurokinins)是一个结构相似的速激肽家族,主要包括P物质(Neurokinin-1, NK1)、神经激肽A(NK2)、神经激肽B(NK3),其生物学效应由相应的NK1、NK2和NK3受体(G蛋白偶联受体)来介导。研究表明神经激肽-神经激肽受体在基底核分布十分丰富,它们与基底核神经元之间存在显著的相互作用,提示神经激肽在基底核生理和病理发生的过程中可能具有重要作用。我们研究组以往的实验已初步证明神经激肽分子能够干预黑质神经元兴奋性毒性损伤,特别是发现神经激肽NK3受体激动剂能产生兴奋性毒性的协同效应。因此,进一步确认神经激肽NK3受体拮抗剂能否调节黑质多巴胺神经元兴奋性毒性损伤,具有重要价值。
本课题采用Fluoro-Jade C(FJC)染色、MPTP(1-methy-4-phenyl-1,2,3,6- tetrahydropyrindine)和KA(Kainic acid,红藻氨酸)损伤动物模型、神经激肽NK3受体特异性拮抗剂干预方法、免疫组织化学染色、动物行为学分析等方法,研究FJC方法在MPTP和KA动物模型中的应用,以及神经激肽NK3受体拮抗剂对黑质多巴胺神经元兴奋性毒性损伤的调节作用。
主要结果:
1.Fluoro-Jade C(FJC)是新出现的荧光染料,与Fluoro-Jade与Fluoro-Jade B的性质相似。我们将FJC染色应用于MPTP和KA损伤小鼠模型,证明FJC染色可以成功显示黑质神经元的变性死亡,是一种简单、敏感、可靠的方法。FJC染色可清晰地显示黑质变性神经元的细胞胞体和突起。在中脑组织切片上,MPTP模型与KA模型黑质致密部内有许多FJC染色阳性的变性神经元,而对照组动物黑质内未见FJC染色阳性的变性神经元分布。
2.采用FJC染色显示变性神经元、TH免疫染色显示存活的多巴胺神经元等方法,分析比较不同处理组的黑质神经元兴奋性毒性损伤情况。结果表明:与单纯KA组相比,NK3受体拮抗剂SB218795与KA共同处理组动物黑质内FJC阳性变性神经元数目明显减少,其动物旋转症状减轻,而TH阳性多巴胺神经元数目明显增加。而单纯NK3受体拮抗剂SB218795处理,未见明显毒性效应。
主要结论:
1.FJC方法能够很好地显示MPTP和KA动物模型黑质内神经元的变性死亡,具备很高的对比度和分辨率,是一种特异性标记黑质变性神经元树突、轴突和胞体的优良染色方法。
2.神经激肽NK3受体拮抗剂能够有效地减轻或抑制KA诱导的黑质多巴胺神经元兴奋性毒性损伤与死亡速度,具有一定的神经保护作用。并进一步证明了神经激肽NK3的兴奋性毒性协同效应。
本研究结果提示神经激肽-受体信号可能是参与PD病理发生的重要因素。神经激肽NK3受体作为一种新的药物干预靶位,具有应用于黑质神经元保护、完善PD治疗的潜在价值。
Parkinson's disease (PD) is one of most common neurodegenerative diseases, which is characterized by serious motor sympotoms such as resting tremor, bradykinesia, rigidity, gait disturbance and postural instability. PD is typically resulted from the massive degenerative death of dopamine neurons in the substantia nigra. Current treatments can not effectively prevent nigral neurons from progressive death and pathogical progress of PD. Previous studies have shown that glutamate-driving excitotoxicity may be one of crucial factors implicating in degeneration of nigral neurons and pathogenesis of PD. It is necessary, thus, to investigate novel strategies on preventing nigral dapamine neurons from excitotoxic lesions and improving the treatment of PD.
Mammalian neurokinins are a family of tachykinin peptides that include substance P (neurokinin-1, NK-1), neurokinin A (NK-2) and neurokinin B (NK-3). Their biological functions are mediated by three distinct G-protein coupled neurokinin receptors, namely SP receptor (NK-1 receptor, NK-1R), neurokinin A receptor (NK-2R) and neurokinin B receptor (NK-3R). Neurokinin peptides and neurokinin receptors are abundantly distributed in the basal ganglia regions and known to significantly interact with neurons of the basal ganglia. Previous evidences had suggested that they may be involved in the regulation of physiological and pathological processes in the basal ganglia circuitry. In previous studies we had found that neurokinin agonists had intervention effects on exitotoxic injuries of nigral dopamine neurons of mice, particularly, administration of NK3 receptor agonist had neurotoxic synergistic effect. Further study is devoted to confirm the synergistic effect of NK3 on excitotoxicity and degenerative death of nigral dopamine neurons.
In the present study, MPTP or KA-induced animal models, Fluoro-Jade C stain, administration of neuronkinin NK3 receptor antagonist, double immunofluorescence, and behavior analysis were applied to confirm effectiveness of FJC staining in the MPTP or KA-lesioned animal models and intervention role of NK3 receptor antagonist in exitotoxic injuries of nigral neurons.
Firstly, Fluoro-Jade C stain can be effectively applied to detect the neuronal degeneration in the substantia nigra of animals induced by MPTP or KA insults, which shows higher resolution and contrast to stain the fine dendrites, axons and cell bodies of the degenerative neurons in the midbrain substantia nigra. In the midbrain tissue sections, FJC-positive degenerative neurons were numerously detected in the substantia nigra pars compacta, whereas they were not seen in the nigral region of control animals.
Secondly, NK3 receptor antagonist effectively decreased KA-induced exitotoxic injuries of nigral dopamine neurons. It revealed that comparison with that of single KA-treated group, pretreatment with NK3 receptor antagonist relieved symptom of animal turning behavior, decreased numbers of FJC-positive degenerative neurons and increased numbers of TH-positive neurons. The data have implied that NK3 receptor antagonist may have certain neuroprotection on dopamine neurons.
Taken together with previous observations, the present results have indicated that neurokinin NK3 signals may play an important role in excitotoxic degeneration of nigral dopamine neurons and pathogenesis of PD. This study also further suggests that NK3 receptor may function as potential therapeutic intervention targets in protecting nigral dopamine neurons and improving treatment of PD in human beings.
神经激肽(Neurokinins)是一个结构相似的速激肽家族,主要包括P物质(Neurokinin-1, NK1)、神经激肽A(NK2)、神经激肽B(NK3),其生物学效应由相应的NK1、NK2和NK3受体(G蛋白偶联受体)来介导。研究表明神经激肽-神经激肽受体在基底核分布十分丰富,它们与基底核神经元之间存在显著的相互作用,提示神经激肽在基底核生理和病理发生的过程中可能具有重要作用。我们研究组以往的实验已初步证明神经激肽分子能够干预黑质神经元兴奋性毒性损伤,特别是发现神经激肽NK3受体激动剂能产生兴奋性毒性的协同效应。因此,进一步确认神经激肽NK3受体拮抗剂能否调节黑质多巴胺神经元兴奋性毒性损伤,具有重要价值。
本课题采用Fluoro-Jade C(FJC)染色、MPTP(1-methy-4-phenyl-1,2,3,6- tetrahydropyrindine)和KA(Kainic acid,红藻氨酸)损伤动物模型、神经激肽NK3受体特异性拮抗剂干预方法、免疫组织化学染色、动物行为学分析等方法,研究FJC方法在MPTP和KA动物模型中的应用,以及神经激肽NK3受体拮抗剂对黑质多巴胺神经元兴奋性毒性损伤的调节作用。
主要结果:
1.Fluoro-Jade C(FJC)是新出现的荧光染料,与Fluoro-Jade与Fluoro-Jade B的性质相似。我们将FJC染色应用于MPTP和KA损伤小鼠模型,证明FJC染色可以成功显示黑质神经元的变性死亡,是一种简单、敏感、可靠的方法。FJC染色可清晰地显示黑质变性神经元的细胞胞体和突起。在中脑组织切片上,MPTP模型与KA模型黑质致密部内有许多FJC染色阳性的变性神经元,而对照组动物黑质内未见FJC染色阳性的变性神经元分布。
2.采用FJC染色显示变性神经元、TH免疫染色显示存活的多巴胺神经元等方法,分析比较不同处理组的黑质神经元兴奋性毒性损伤情况。结果表明:与单纯KA组相比,NK3受体拮抗剂SB218795与KA共同处理组动物黑质内FJC阳性变性神经元数目明显减少,其动物旋转症状减轻,而TH阳性多巴胺神经元数目明显增加。而单纯NK3受体拮抗剂SB218795处理,未见明显毒性效应。
主要结论:
1.FJC方法能够很好地显示MPTP和KA动物模型黑质内神经元的变性死亡,具备很高的对比度和分辨率,是一种特异性标记黑质变性神经元树突、轴突和胞体的优良染色方法。
2.神经激肽NK3受体拮抗剂能够有效地减轻或抑制KA诱导的黑质多巴胺神经元兴奋性毒性损伤与死亡速度,具有一定的神经保护作用。并进一步证明了神经激肽NK3的兴奋性毒性协同效应。
本研究结果提示神经激肽-受体信号可能是参与PD病理发生的重要因素。神经激肽NK3受体作为一种新的药物干预靶位,具有应用于黑质神经元保护、完善PD治疗的潜在价值。
Parkinson's disease (PD) is one of most common neurodegenerative diseases, which is characterized by serious motor sympotoms such as resting tremor, bradykinesia, rigidity, gait disturbance and postural instability. PD is typically resulted from the massive degenerative death of dopamine neurons in the substantia nigra. Current treatments can not effectively prevent nigral neurons from progressive death and pathogical progress of PD. Previous studies have shown that glutamate-driving excitotoxicity may be one of crucial factors implicating in degeneration of nigral neurons and pathogenesis of PD. It is necessary, thus, to investigate novel strategies on preventing nigral dapamine neurons from excitotoxic lesions and improving the treatment of PD.
Mammalian neurokinins are a family of tachykinin peptides that include substance P (neurokinin-1, NK-1), neurokinin A (NK-2) and neurokinin B (NK-3). Their biological functions are mediated by three distinct G-protein coupled neurokinin receptors, namely SP receptor (NK-1 receptor, NK-1R), neurokinin A receptor (NK-2R) and neurokinin B receptor (NK-3R). Neurokinin peptides and neurokinin receptors are abundantly distributed in the basal ganglia regions and known to significantly interact with neurons of the basal ganglia. Previous evidences had suggested that they may be involved in the regulation of physiological and pathological processes in the basal ganglia circuitry. In previous studies we had found that neurokinin agonists had intervention effects on exitotoxic injuries of nigral dopamine neurons of mice, particularly, administration of NK3 receptor agonist had neurotoxic synergistic effect. Further study is devoted to confirm the synergistic effect of NK3 on excitotoxicity and degenerative death of nigral dopamine neurons.
In the present study, MPTP or KA-induced animal models, Fluoro-Jade C stain, administration of neuronkinin NK3 receptor antagonist, double immunofluorescence, and behavior analysis were applied to confirm effectiveness of FJC staining in the MPTP or KA-lesioned animal models and intervention role of NK3 receptor antagonist in exitotoxic injuries of nigral neurons.
Firstly, Fluoro-Jade C stain can be effectively applied to detect the neuronal degeneration in the substantia nigra of animals induced by MPTP or KA insults, which shows higher resolution and contrast to stain the fine dendrites, axons and cell bodies of the degenerative neurons in the midbrain substantia nigra. In the midbrain tissue sections, FJC-positive degenerative neurons were numerously detected in the substantia nigra pars compacta, whereas they were not seen in the nigral region of control animals.
Secondly, NK3 receptor antagonist effectively decreased KA-induced exitotoxic injuries of nigral dopamine neurons. It revealed that comparison with that of single KA-treated group, pretreatment with NK3 receptor antagonist relieved symptom of animal turning behavior, decreased numbers of FJC-positive degenerative neurons and increased numbers of TH-positive neurons. The data have implied that NK3 receptor antagonist may have certain neuroprotection on dopamine neurons.
Taken together with previous observations, the present results have indicated that neurokinin NK3 signals may play an important role in excitotoxic degeneration of nigral dopamine neurons and pathogenesis of PD. This study also further suggests that NK3 receptor may function as potential therapeutic intervention targets in protecting nigral dopamine neurons and improving treatment of PD in human beings.
引文
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[17] Zuch CL, Nordstroem VK, Briedrick LA, et al. Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. J Comp Neurol, 2000; 427:440-454.
[18] Ye X, Carp RI, Schmued LC, et al. Fluoro-Jade and silver methods: application to the neuropathology of scrapie, a transmissible spongiform encephalopathy. Brain Res Protoc, 2001; 8:104-112.
[1] Michaelis EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog.Neurobiol, 1998; 54:369-415.
[2] Chen LW, Guan ZL, Ding YQ. Mesencephalic dopaminergic neurons expressing neuromedin K receptor (NK3): a double immunocytochemical study in the rat. Brain Res, 1998; 780:150-154.
[3] Chen LW, Wei LC, Lang B, Ju G, Chan YS. Differential expression of AMPA receptor subunits I n dopamine neurons of the rat brain: a double immunocytochemical study. Neuroscience, 2001; 106:149-160.
[4] Chen LW, Wei LC, Liu HL et al. Cholinergic neurons expressing neuromedin K receptor (NK3) in the basal forebrain of the rat: a double immunofluorescence study. Neuroscience, 2001; 103: 413-422.
[5] Albers DS, Weiss SW, Iadarola MJ, Standaert DG. Immunohistochemical localization of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate receptor subunits in the substantia nigra pars compacta of the rat. Neuroscience, 1999; 89:209-220.
[6] Paquet M, Tremblay M, Soghomonian JJ, Smith Y. AMPA and NMDA glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey: an immunohistochemical and in situ hybridization study. Neurosci, 1997; 17:1377-1396.
[7] Tse YC, Yung KK. Cellular expression of ionotropic glutamate receptor subunitsin subpopulations of neurons in the rat substantia nigra pars reticulata. Brain Res, 2000; 854:57-69.
[8] Wullner U, Standaert DG, Testa CM, Penney JB, Young AB. Differential expression of kainate receptors in the basal ganglia of the developing and adult rat brain. Brain Res, 1997; 768: 215-223.
[9] Hopkins KJ, Wang G, Schmued LC. Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain. Brain Res, 2000; 864:69-80.
[10] Johnson SM, Luo X, Bywood PT. Neurotoxic effects of kainic acid on substantia nigra neurons in rat brain slices. Exp Neurol, 1997; 146:546-552.
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[13] Futami T, Hatanaka Y, Matsushita K, Furuya S. Expression of substance P receptor in the substantia nigra. Brain Res, 1998; 54:183-198.
[14] Nakaya Y, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. Comp Neurol, 1994; 347: 249-274.
[15] Freyaldenhoven TE, Ali SF, Schmued LC. Systemic administration of MPTP induces thalamic neuronal degeneration in mice. Brain Res, 1997; 759:9-17.
[16] Schmued LC, Hopkins KJ. Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res, 2000; 874:123-130.
[17] Zuch CL, Nordstroem VK, Briedrick LA, Hoernig GR, Granholm AC, Bickford PC. Time courseof degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. Comp Neurol, 2000; 427:440-454.
[18] Schmued LC, Stowers CC, Scallet AC et al. Fluoro-Jade C results in ultra high resolution and contrast labeiing of degenerating neurons. Brain Res, 2005; 1035:24-31
[19] 曹荣,扈慧静,王艳芹,张金萍,陈良为.Fluoro-Jade B 法显示神经毒物红藻氨酸和 MPTP致小鼠基底神经核损伤引起神经元的变性死亡.解剖学报,2005; 36:452-455.
[20] Schmued LC, Albertson C, Slikker W J. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res, 1997; 751:37-46.
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[1] Schmued LC, Albertson C, Slikker W Jr. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res, 1997; 751:37-46.
[2] Schmued LC, Hopkins KJ. Fluoro-Jade: novel fluorochromes for detecting toxicant-induced neuronal degeneration. Toxicol Pathol, 2000; 28:91-99.
[3] Schmued LC, Hopkins KJ. Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res, 2000; 874:123-130.
[4] Chen LW, Zhang JP, Shum DKY et al. Localization of NGF, NT3 and GDNF in nestin-expressing reactive astrocytes in the caudate-putamen of MPTP-treated C57/BL mice. J Comp Neurol, 2006; 497:898-909.
[5] 曹荣,扈慧静,王艳芹等.Fluoro-Jade B 法显示神经毒物红藻氨酸和 MPTP 致小鼠基底神经核损伤引起的神经元变性死亡.中国解剖学报, 2005; 36:452-455.
[6] Schmued LC, Stowers CC, Scallet AC et al. Fluoro-Jade C results in ultra high resolution andcontrast labeiing of degenerating neurons. Brain Res, 2005; 1035:24-31.
[7] Chen LW, Hu HJ, Liu HL, et al. Identification of BDNF in nestin-expressing astroglial cells in the neostriatum of MPTP-treated mice. Neuroscience, 2004; 126:941-953.
[8] Chen LW, Wei LC, Qiu Y, et al. Significant up-regulation of nestin protein in the neostriatum of MPTP-treated mice: are the striatal astrocytes regionally activated after systemic MPTP administration? Brain Res, 2002; 925:9-17.
[9] Hopkins KJ, Wang G, Schmued LC. Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain. Brain Res, 2000; 864:69-80.
[10] Ballok DA, Millward JM, Sakic B. Neurodegeneration in autoimmune MRL-lpr mice as revealed by Fluoro Jade B staining. Brain Res, 2003; 964:200-210.
[11] Butler TL, Kassed CA, Sanberg PR et al. Neurodegeneration in the rat hippocampus and striatum after middle cerebral artery occlusion. Brain Res, 2002; 929:252-260.
[12] Eyupoglu IY, Savaskan NE, Brauer AU, et al. Identification of neuronal cell death in a model of degeneration in the hippocampus. Brain Res Protoc, 2003; 11:1-8.
[13] Kassed CA, Willing AE, Garbuzova-Davis S, et al. Lack of NF-kappa B p50 exacerbates degeneration of hippocampal neurons after chemical exposure and impairs learning. Exp Neurol, 2002; 176:277-288.
[14] Kubova H, Druga R, Lukasiuk K, et al. Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. J Neurosci, 2001; 21:3593-3599.
[15] Narkilahti S, Pirttila TJ, Lukasiuk K, et al. Expression and activation of caspase-3 following status epilepticus in the rat. Eur J Neurosci, 2003; 18:1486-1496.
[16] Pitkanen A, Nissinen J, Nairismagi J, et al. Progression of neuronal damage after status epilepticus and during spontaneous seizures in a rat model of temporal lobe epilepsy. Prog Brain Res, 2002; 135:67-83.
[17] Zuch CL, Nordstroem VK, Briedrick LA, et al. Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. J Comp Neurol, 2000; 427:440-454.
[18] Ye X, Carp RI, Schmued LC, et al. Fluoro-Jade and silver methods: application to the neuropathology of scrapie, a transmissible spongiform encephalopathy. Brain Res Protoc, 2001; 8:104-112.
[1] Michaelis EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog.Neurobiol, 1998; 54:369-415.
[2] Chen LW, Guan ZL, Ding YQ. Mesencephalic dopaminergic neurons expressing neuromedin K receptor (NK3): a double immunocytochemical study in the rat. Brain Res, 1998; 780:150-154.
[3] Chen LW, Wei LC, Lang B, Ju G, Chan YS. Differential expression of AMPA receptor subunits I n dopamine neurons of the rat brain: a double immunocytochemical study. Neuroscience, 2001; 106:149-160.
[4] Chen LW, Wei LC, Liu HL et al. Cholinergic neurons expressing neuromedin K receptor (NK3) in the basal forebrain of the rat: a double immunofluorescence study. Neuroscience, 2001; 103: 413-422.
[5] Albers DS, Weiss SW, Iadarola MJ, Standaert DG. Immunohistochemical localization of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate receptor subunits in the substantia nigra pars compacta of the rat. Neuroscience, 1999; 89:209-220.
[6] Paquet M, Tremblay M, Soghomonian JJ, Smith Y. AMPA and NMDA glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey: an immunohistochemical and in situ hybridization study. Neurosci, 1997; 17:1377-1396.
[7] Tse YC, Yung KK. Cellular expression of ionotropic glutamate receptor subunitsin subpopulations of neurons in the rat substantia nigra pars reticulata. Brain Res, 2000; 854:57-69.
[8] Wullner U, Standaert DG, Testa CM, Penney JB, Young AB. Differential expression of kainate receptors in the basal ganglia of the developing and adult rat brain. Brain Res, 1997; 768: 215-223.
[9] Hopkins KJ, Wang G, Schmued LC. Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain. Brain Res, 2000; 864:69-80.
[10] Johnson SM, Luo X, Bywood PT. Neurotoxic effects of kainic acid on substantia nigra neurons in rat brain slices. Exp Neurol, 1997; 146:546-552.
[11] Arnt J. Turning behaviour and catalepsy after injection of excitatory amino acids into rat substantia nigra. Neurosci Lett, 1981; 23:337-342.
[12] Ding YQ, Shigemoto R, Takada M, Ohishi H, Nakanishi S, Mizuno N. Localization of the neuromedin K receptor (NK3) in the central nervous system of the rat. J.Comp Neurol, 1996; 364:290-310.
[13] Futami T, Hatanaka Y, Matsushita K, Furuya S. Expression of substance P receptor in the substantia nigra. Brain Res, 1998; 54:183-198.
[14] Nakaya Y, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. Comp Neurol, 1994; 347: 249-274.
[15] Freyaldenhoven TE, Ali SF, Schmued LC. Systemic administration of MPTP induces thalamic neuronal degeneration in mice. Brain Res, 1997; 759:9-17.
[16] Schmued LC, Hopkins KJ. Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res, 2000; 874:123-130.
[17] Zuch CL, Nordstroem VK, Briedrick LA, Hoernig GR, Granholm AC, Bickford PC. Time courseof degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. Comp Neurol, 2000; 427:440-454.
[18] Schmued LC, Stowers CC, Scallet AC et al. Fluoro-Jade C results in ultra high resolution and contrast labeiing of degenerating neurons. Brain Res, 2005; 1035:24-31
[19] 曹荣,扈慧静,王艳芹,张金萍,陈良为.Fluoro-Jade B 法显示神经毒物红藻氨酸和 MPTP致小鼠基底神经核损伤引起神经元的变性死亡.解剖学报,2005; 36:452-455.
[20] Schmued LC, Albertson C, Slikker W J. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res, 1997; 751:37-46.
[21] Whiteside G, Cougnon N, Hunt SP, Munglani R. An improved method for detection of apoptosis in tissue sections and cell culture, using the TUNEL technique combined with Hoechst stain. Brain Res Protoco, 1998; 2:160-164.
[22] Ye X, Carp RI, Schmued LC, Scallet AC. Fluoro-Jade and silver methods: application to the neuropathology of scrapie, a transmissible spongiform encephalopathy. Brain Res Protoc, 2001; 8:104-112.
[23] Randic M, Hecinovic H, Ryu PD. Substance P modulates glutamate-induced currents in acutely isolated rat spinal dorsal horn neurones. Neurosci Lett, 1990; 117:74–80.
[24] Rusin KI, Bleakman D, Chard PS, Randic M, Miller RJ. Tachykinins potentiate N-methyl-D-aspartate responses in acutely isolated neurons from the dorsal horn. Neurochem, 1993; 60:952–960.
[25] Rusin KI, Jiang MC, Cerne R, Randic M. Interactions between the excitatory amino acids and tachykinins in the rat spinal dorsal horn. Brain Res Bull, 1993; 30:329–338.
[26] Lieberman DN and Mody I. Substance P enhances NMDA channel function in hippocampal dentate gyrus granule cells. Neurophysiol, 1998; 80:113–119.
[27] Kemel Ml, Pe′rez S, Godeheu G, Soubrie′ P and Glowinski J. Facilitation by endogenous tachykinins of the NMDA-evoked release of acetylcholine after acute and chronic suppression of dopaminergic transmission in the matrix of the rat striatum. Neurosci, 2002; 22:1929–1936.
[28] Marvizon JC, Martinez V, Grady EF, Bunnett NW, Mayer EA. Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. Neurosci, 1997, 17:8129-36.