小胶质细胞与神经退行性疾病——机制与相应治疗药物探讨
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摘要
小胶质细胞是大脑的免疫细胞,在成熟脑静止的小胶质细胞呈分枝状,主要起免疫监视作用。作为脑中的重要防线,当应对脑损伤或免疫原刺激时很容易活化。活化的小胶质细胞经历了戏剧性的变化,其形态由静止的分枝状变为活化的变形虫状。其表面分子如补体受体和组织相容性蛋白的表达增加。同时,激活的小胶质细胞释放多种可溶性因子。尽管已知小胶质细胞可释放神经营养因子,但其释放的大多数因子是具有潜在的细胞毒作用的前致炎因子。几种常见神经退行性疾病,包括帕金森和阿茨海默症与脑内免疫细胞-小胶质细胞相关,小胶质细胞介导的炎症在神经退行性疾病的病理过程中起了重要作用。当外界致炎原(如Beta-amyloid peptide A β或Lipopolysaccharide LPS)加在神经-胶质细胞混合培养中后,在小胶质细胞产生的诸多因子如TNF-α,IL-β,一氧化氮和超氧化物中,出现最早的是超氧离子。因此超氧离子的作用不容低估。本工作以Aβ或LPS为致炎原,探讨了激活的小胶质细胞中NADPH氧化酶产生的超氧离子的重要作用。我们还发现了纳洛酮和右旋美沙芬在抑制超氧离子产生的作用,为开发由氧化应激导致的神经退行性等诸多疾病的预防和治疗药物提供了依据。
一.小胶质细胞增强β-Amyloid多肽诱导的神经毒性
本研究的目的是比较与评价β-Amyloid多肽(Aβ)对含有与不含有小胶质细胞的皮质或中脑神经-胶质细胞培养体系的毒性,以及探讨小胶质细胞介导的神经毒性的机制。用0.1-6.0μM的Aβ分别处理来自皮质或中脑的纯神经元原代培养,Aβ引起了浓度依赖性神经毒性。在纯神经培养中,高浓度的Aβ直接损伤神经元。在小胶质细胞与神经细胞混合培养中,较低浓度的Aβ(皮层神经细胞1.0-3.0μM,中脑神经细胞0.25-1.0)即可产生明显的神经毒性。但在纯神经培养体系则未见到毒性。许多证据表明,小胶质细胞介导Aβ引起的神经毒性。在神经-小胶质细胞混合培养体系或在人为加入更多小胶质细胞的神经-小胶质细胞培养体系中的数据显示,小胶质细胞增加了Aβ诱导的神经毒性。为了探讨小胶质细胞介导的神经毒性机制,我们对几个致炎因子进行了测定。低浓度的Aβ明显增强了超氧离子的产生,但不增加肿瘤坏死因子-α(TNF-α),白介素-1β(IL-1
摘要
刀)和一氧化氮(NO)的产生。在小胶质细胞存在下,超氧化物企化酶(S OD)
明显降低Ap诱导的神经毒性。研究证实,NADPH氧化酶产生的超氧化物在介
导Ap诱导的神经毒性中起了关键作用。在中脑神经一胶质细胞培养体系中,Ap
引起多巴胺摄取能力的降低,敲除(knock out) NADPH氧化酶亚基gP”,基因的
小鼠与正常小鼠比较,两者有显著性差异。本研究证实,小胶质细胞增加Ap诱
导的神经毒性的机制之一是通过诱导ROS的产生。
二.纳洛酮及其立体异构体抑制p~Amyloid多肤诱导小胶质细胞产生超氧自
由基以及脑皮质和中脑神经元的变性
纳洛酮及其立体异构体以非依赖性阿片受体的方式,通过抑制脑内免疫细胞
一小胶质细胞的激活降低了炎症介导的多巴胺神经元的退化。本研究的目的在于检
测纳洛酮及其立体异构体对Ap(1一42)诱导的神经退化是否有作用。用卜10“
M(一)纳洛酮预处理皮层或中脑神经一小胶质细胞培养,然后加入0.1一0.3 p MA
p(1一42),继续培养n天。通过检测DA或GABA摄取能力、细胞免疫染色、
及细胞计数分析,发现纳洛酮具有明显的神经保护作用。更重要的是,与阿片受
体不结合的(+)纳洛酮和(一)纳洛酮具有同样的神经保护作用。纳洛酮及其立
体异构体的神经保护作用在于其抑制Ap(1一42)诱导小胶质细胞产生超氧自由
基。而且,纳洛酮的衍生物一带正电荷的NM(naloxone methiodide)也同样具有
这种保护和抑制作用。这说明纳洛酮及其立体异构体的结合位点位于小胶质细胞
的表面。这些结果证明纳洛酮及其立体异构体通过非阿片受体的机制,抑制了A
p(1一42)诱导的小胶质细胞的激活,保护了脑皮层或中脑神经原细胞的退化。
结合我们先前发现纳洛酮及其立体异构体对致炎原诱导的神经退化的作用,我们
认为,纳洛酮类似物,特别是(+)纳洛酮是潜在的治疗老年性痴呆和帕金森病
的药物。
三.右旋美沙芬(DM)对炎症介导的多巴胺神经元退化的保护作用
脑内炎症反应在几种神经退化性疾病病理进展中起着重要的作用,这些疾病
包括帕金森病和老年性痴呆。炎症介导的神经变性与脑内免疫细胞一小胶质细胞的
激活有关,活化的小胶质细胞释放各种免疫因子和神经毒素,包括肿瘤坏死因子
一a(T哪一a),白介素一lp(IL一lp),花生四烯酸代谢产物,一氧化氮(NO)和反
应胜氧自由基(reaetive oxygen speeies ROS)。这些因子作用于神经细胞引起神经
大连理工大学博士学位论文
元变性死亡。因此,确定抑制小胶质细胞激活的化合物是寻找治疗炎症介导的神
经退化性疾病药物的有效途径。本研究中我们发现,DM(一种临床上广泛使用
的止咳药)通过阻止小胶质细胞的激活有效的降低了炎症介导的多巴胺神经元的
变性。用DM(1一10林M)预处理大鼠中脑神经细胞一胶质细胞混合培养体系30分
钟,有效的降低了LPs(10n岁ml)诱导的多巴胺神经元的变性。更重要的是,如
果在细胞培养中加入LPS60分钟后再加入DM,仍可见到非常明显的神经保护作
用。DM对L
Microglia are the resident immune cells in the brain, in mature brains, Resting microglia exhibit a characteristic ramified morphology and serve the critical role of immune surveillance. As an important line of defense in the brain, microglia become readily activated in reponse to injuries to the brain or to the immunologic stimuli. Activated microglia undergo dramatic morphologic changes, metamorphosing from resting ramified microglia into activated amoeboid microglia. They also exhibit increased expression of surface molecules such as complement receptor sand major histocompatibility complex (MHC) molecules. At the same time, Activated microglia release a variety of soluble factors. Although activated microglia are knovra to produce several trophic factors, most of the factors relased by activated microglia are proinflammatory and potentially cytotoxic. Several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are associated with immunocompetent microglia, leading to the suggestion that chronic glial-mediated inflammation contributes to the neurodegeneration seen in these diseases. Add A β or LPS in neuron-glia cell cultures, activated microglia release variety of proinflammatory factors including TNF α ,interleukin-1β, nitric oxide and superoxide. Superoxide is the earliest one among these proinflammatory factors. So the effect of superoxide on neurodegeneration can not be undervalued. In this study, using A β or LPS, we investigated the important role of superoxide generated from NADPH oxidase in the activation of microgli. We also demonstrated that DM and Naloxone significantly reduce the production of superoxide. This afford the strategy for the treatment of nerodegenerative dease. . Microglia enhance A β -induced toxicity in cortical and mesencephalic neurons: The purpose of this study was to assess and compare, for the first time, the toxicity of Aβ on primary cortical and mesencephalic neurons cultured with and without microglia in an effort to determine the mechanism for microglia-mediated Ap-induced neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched and mixed neuron-glia cultures with Aβ (1-42) over the concentration range of 0.1-6.0
μM caused a concentration-dependent neurotoxicity. High concentrations of Aβ (6.0 μM for cortex and 1.5-2.0 μM for mesencephalon) directly injured neurons in neuron-enriched cultures. In contrast, lower concentrations of Aβ (1.0-3.0 μM for cortex and 0.25-1.0 μM for mesencephalon) caused significant neurotoxicity in the mixed neuron-glia cultures, but not in the neuron-enriched cultures. Several lines of evidence are provided that microglia mediated the potentiated neurotoxicity of Aβ including: low concentrations of Aβ activated microglia morphologically in neuron-glia cultures; and addition of microglia to cortical neuron-glia cultures enhanced Aβ-induced neurotoxicity. To search for the mechanism underlying the microglia mediated effects, several proinflammatory factors were determined in neuron-glia cultures. Low doses of Aβ significantly increased the production of superoxide anions, but not tumor necrosis factor α, interleukin-1β, or nitric oxide. Catalase and superoxide dismutase significantly protected neurons from Aβ toxicity in the presence of microglia. Furthermore, inhibition of NADPH oxidase activity by diphenyleneiodonium also prevented Aβ-induced neurotoxicity in neuron-glia mixed cultures. This study demonstrates that one of the mechanisms by which microglia can enhance the neurotoxicity of Aβ is via the production of reactive oxygen species.2. Inhibition by naloxone stereoisomers of Aβ-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons: Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, prevented the infiammagen-induced degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain.Recently we discovered that beta-amyloid pepti
一.小胶质细胞增强β-Amyloid多肽诱导的神经毒性
本研究的目的是比较与评价β-Amyloid多肽(Aβ)对含有与不含有小胶质细胞的皮质或中脑神经-胶质细胞培养体系的毒性,以及探讨小胶质细胞介导的神经毒性的机制。用0.1-6.0μM的Aβ分别处理来自皮质或中脑的纯神经元原代培养,Aβ引起了浓度依赖性神经毒性。在纯神经培养中,高浓度的Aβ直接损伤神经元。在小胶质细胞与神经细胞混合培养中,较低浓度的Aβ(皮层神经细胞1.0-3.0μM,中脑神经细胞0.25-1.0)即可产生明显的神经毒性。但在纯神经培养体系则未见到毒性。许多证据表明,小胶质细胞介导Aβ引起的神经毒性。在神经-小胶质细胞混合培养体系或在人为加入更多小胶质细胞的神经-小胶质细胞培养体系中的数据显示,小胶质细胞增加了Aβ诱导的神经毒性。为了探讨小胶质细胞介导的神经毒性机制,我们对几个致炎因子进行了测定。低浓度的Aβ明显增强了超氧离子的产生,但不增加肿瘤坏死因子-α(TNF-α),白介素-1β(IL-1
摘要
刀)和一氧化氮(NO)的产生。在小胶质细胞存在下,超氧化物企化酶(S OD)
明显降低Ap诱导的神经毒性。研究证实,NADPH氧化酶产生的超氧化物在介
导Ap诱导的神经毒性中起了关键作用。在中脑神经一胶质细胞培养体系中,Ap
引起多巴胺摄取能力的降低,敲除(knock out) NADPH氧化酶亚基gP”,基因的
小鼠与正常小鼠比较,两者有显著性差异。本研究证实,小胶质细胞增加Ap诱
导的神经毒性的机制之一是通过诱导ROS的产生。
二.纳洛酮及其立体异构体抑制p~Amyloid多肤诱导小胶质细胞产生超氧自
由基以及脑皮质和中脑神经元的变性
纳洛酮及其立体异构体以非依赖性阿片受体的方式,通过抑制脑内免疫细胞
一小胶质细胞的激活降低了炎症介导的多巴胺神经元的退化。本研究的目的在于检
测纳洛酮及其立体异构体对Ap(1一42)诱导的神经退化是否有作用。用卜10“
M(一)纳洛酮预处理皮层或中脑神经一小胶质细胞培养,然后加入0.1一0.3 p MA
p(1一42),继续培养n天。通过检测DA或GABA摄取能力、细胞免疫染色、
及细胞计数分析,发现纳洛酮具有明显的神经保护作用。更重要的是,与阿片受
体不结合的(+)纳洛酮和(一)纳洛酮具有同样的神经保护作用。纳洛酮及其立
体异构体的神经保护作用在于其抑制Ap(1一42)诱导小胶质细胞产生超氧自由
基。而且,纳洛酮的衍生物一带正电荷的NM(naloxone methiodide)也同样具有
这种保护和抑制作用。这说明纳洛酮及其立体异构体的结合位点位于小胶质细胞
的表面。这些结果证明纳洛酮及其立体异构体通过非阿片受体的机制,抑制了A
p(1一42)诱导的小胶质细胞的激活,保护了脑皮层或中脑神经原细胞的退化。
结合我们先前发现纳洛酮及其立体异构体对致炎原诱导的神经退化的作用,我们
认为,纳洛酮类似物,特别是(+)纳洛酮是潜在的治疗老年性痴呆和帕金森病
的药物。
三.右旋美沙芬(DM)对炎症介导的多巴胺神经元退化的保护作用
脑内炎症反应在几种神经退化性疾病病理进展中起着重要的作用,这些疾病
包括帕金森病和老年性痴呆。炎症介导的神经变性与脑内免疫细胞一小胶质细胞的
激活有关,活化的小胶质细胞释放各种免疫因子和神经毒素,包括肿瘤坏死因子
一a(T哪一a),白介素一lp(IL一lp),花生四烯酸代谢产物,一氧化氮(NO)和反
应胜氧自由基(reaetive oxygen speeies ROS)。这些因子作用于神经细胞引起神经
大连理工大学博士学位论文
元变性死亡。因此,确定抑制小胶质细胞激活的化合物是寻找治疗炎症介导的神
经退化性疾病药物的有效途径。本研究中我们发现,DM(一种临床上广泛使用
的止咳药)通过阻止小胶质细胞的激活有效的降低了炎症介导的多巴胺神经元的
变性。用DM(1一10林M)预处理大鼠中脑神经细胞一胶质细胞混合培养体系30分
钟,有效的降低了LPs(10n岁ml)诱导的多巴胺神经元的变性。更重要的是,如
果在细胞培养中加入LPS60分钟后再加入DM,仍可见到非常明显的神经保护作
用。DM对L
Microglia are the resident immune cells in the brain, in mature brains, Resting microglia exhibit a characteristic ramified morphology and serve the critical role of immune surveillance. As an important line of defense in the brain, microglia become readily activated in reponse to injuries to the brain or to the immunologic stimuli. Activated microglia undergo dramatic morphologic changes, metamorphosing from resting ramified microglia into activated amoeboid microglia. They also exhibit increased expression of surface molecules such as complement receptor sand major histocompatibility complex (MHC) molecules. At the same time, Activated microglia release a variety of soluble factors. Although activated microglia are knovra to produce several trophic factors, most of the factors relased by activated microglia are proinflammatory and potentially cytotoxic. Several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are associated with immunocompetent microglia, leading to the suggestion that chronic glial-mediated inflammation contributes to the neurodegeneration seen in these diseases. Add A β or LPS in neuron-glia cell cultures, activated microglia release variety of proinflammatory factors including TNF α ,interleukin-1β, nitric oxide and superoxide. Superoxide is the earliest one among these proinflammatory factors. So the effect of superoxide on neurodegeneration can not be undervalued. In this study, using A β or LPS, we investigated the important role of superoxide generated from NADPH oxidase in the activation of microgli. We also demonstrated that DM and Naloxone significantly reduce the production of superoxide. This afford the strategy for the treatment of nerodegenerative dease. . Microglia enhance A β -induced toxicity in cortical and mesencephalic neurons: The purpose of this study was to assess and compare, for the first time, the toxicity of Aβ on primary cortical and mesencephalic neurons cultured with and without microglia in an effort to determine the mechanism for microglia-mediated Ap-induced neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched and mixed neuron-glia cultures with Aβ (1-42) over the concentration range of 0.1-6.0
μM caused a concentration-dependent neurotoxicity. High concentrations of Aβ (6.0 μM for cortex and 1.5-2.0 μM for mesencephalon) directly injured neurons in neuron-enriched cultures. In contrast, lower concentrations of Aβ (1.0-3.0 μM for cortex and 0.25-1.0 μM for mesencephalon) caused significant neurotoxicity in the mixed neuron-glia cultures, but not in the neuron-enriched cultures. Several lines of evidence are provided that microglia mediated the potentiated neurotoxicity of Aβ including: low concentrations of Aβ activated microglia morphologically in neuron-glia cultures; and addition of microglia to cortical neuron-glia cultures enhanced Aβ-induced neurotoxicity. To search for the mechanism underlying the microglia mediated effects, several proinflammatory factors were determined in neuron-glia cultures. Low doses of Aβ significantly increased the production of superoxide anions, but not tumor necrosis factor α, interleukin-1β, or nitric oxide. Catalase and superoxide dismutase significantly protected neurons from Aβ toxicity in the presence of microglia. Furthermore, inhibition of NADPH oxidase activity by diphenyleneiodonium also prevented Aβ-induced neurotoxicity in neuron-glia mixed cultures. This study demonstrates that one of the mechanisms by which microglia can enhance the neurotoxicity of Aβ is via the production of reactive oxygen species.2. Inhibition by naloxone stereoisomers of Aβ-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons: Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, prevented the infiammagen-induced degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain.Recently we discovered that beta-amyloid pepti
引文
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26. Gonzalez-Scarano F, Baltuch G Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci. 1999 22: 219-240.
27. Minghetti L and Levi G Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol. 1998 54(1): 99-125.
28. Streit WJ. Microglial response to brain injury: a brief synopsis. Toxicol Pathol. 2000 28(1): 28-30.
29. Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS. NADPH oxidase mediates LPS-induced neurotoxicity and pro-inflammatory gene expression in activated microglia. J Biol Chem. 2003 Oct 24 [Epub ahead of print]
30. Liu B, Du L and Hong JS Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Phar Exp Ther 2000a 293: 607-617.
31. Liu B, Jiang JW, Wilson BC, Du L, Yang SN, Wang JY, Wu GC, Cao XD and Hong JS Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther 2000b 295: 125-132
32. Lu X, Bing G, Hagg T. Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience. 2000 97(2): 285-91.
33. Tortella FC, Pellicano M and Bowery NG Dextromethorphan and neuromodulation: old drug coughs up new activities. Trends Pharmacol Sci 1989 10:501-507.
34. George CP, Goldberg MP, Choi DW and Steinberg GK Dextromethorphan reduces neocortical ischemic neuronal damage in vivo. Brain Res 1988 440:375-379.
35. Monyer H and Choi DW Morphinans attenuate cortical neuronal injury induced by glucose deprivation in vitro. Brain Res 1988 446:144-148.
36. Prince DA and Feeser HRD extromethorphan protects against cerebral infarction in a rat model of hypoxia-ischemia. Neurosci Lett 1988 85:291-296.
37. Steinberg GK, George CP, DeLaPaz R, Shibata DK and Gross T Dextromethorphan protects against cerebral injury following transient focal ischemia in rabbits. Stroke 1988 19:1112-1118.
38. Britton P, Lu XC, Laskosky MS and Tortella FC Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats. Life Sci 1997 60:1729-1740.
39. Tortella FC, Britton P, Williams A, Lu XC and Newman AH Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist. J Pharmacol Exp Ther 1999 291:399-408.
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44. Haberecht MF, Mitchell CK, Lo GJ and Redburn DA N-methyl-D-aspartate-mediated glutamate toxicity in the developing rabbit retina. J Neurosci Res 1997 47:416-426.
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23. Raine CS Multiple sclerosis: immune system molecule expression in the central nervous system. J. Neuropathol. Exp. Neurol 1994 53: 328-337
24. Hirsch EC. Glial cells and Parkinson's disease. J neurol.2000 247: 1158-1162
25. Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, Howells DW. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci. 1999 19(5): 1708-1716.
26. Gonzalez-Scarano F, Baltuch G Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci. 1999 22: 219-240.
27. Minghetti L and Levi G Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol. 1998 54(1): 99-125.
28. Streit WJ. Microglial response to brain injury: a brief synopsis. Toxicol Pathol. 2000 28(1): 28-30.
29. Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS. NADPH oxidase mediates LPS-induced neurotoxicity and pro-inflammatory gene expression in activated microglia. J Biol Chem. 2003 Oct 24 [Epub ahead of print]
30. Liu B, Du L and Hong JS Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Phar Exp Ther 2000a 293: 607-617.
31. Liu B, Jiang JW, Wilson BC, Du L, Yang SN, Wang JY, Wu GC, Cao XD and Hong JS Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther 2000b 295: 125-132
32. Lu X, Bing G, Hagg T. Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience. 2000 97(2): 285-91.
33. Tortella FC, Pellicano M and Bowery NG Dextromethorphan and neuromodulation: old drug coughs up new activities. Trends Pharmacol Sci 1989 10:501-507.
34. George CP, Goldberg MP, Choi DW and Steinberg GK Dextromethorphan reduces neocortical ischemic neuronal damage in vivo. Brain Res 1988 440:375-379.
35. Monyer H and Choi DW Morphinans attenuate cortical neuronal injury induced by glucose deprivation in vitro. Brain Res 1988 446:144-148.
36. Prince DA and Feeser HRD extromethorphan protects against cerebral infarction in a rat model of hypoxia-ischemia. Neurosci Lett 1988 85:291-296.
37. Steinberg GK, George CP, DeLaPaz R, Shibata DK and Gross T Dextromethorphan protects against cerebral injury following transient focal ischemia in rabbits. Stroke 1988 19:1112-1118.
38. Britton P, Lu XC, Laskosky MS and Tortella FC Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats. Life Sci 1997 60:1729-1740.
39. Tortella FC, Britton P, Williams A, Lu XC and Newman AH Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist. J Pharmacol Exp Ther 1999 291:399-408.
40. Choi DW Dextrorphan and dextromethorphan attenuate glutamate neurotoxicity. Brain Res 1987403:333-336.
41. DeCoster MA, Klette KL, Knight ES and Tortella FC Sigma receptor-mediated neuroprotection against glutamate toxicity in primary rat neuronal cultures. Brain Res 1995 671:45-53.
42. Lesage AS, De Loore KL, Peeters L and Leysen JE Neuroprotective sigma ligands interfere with the glutamate-activated NOS pathway in hippocampal cell culture. Synapse 1995 20:156-164.
43. Berman FW and Murray TF Characterization of [3H]MK-801 binding to N-methyl-D-aspartate receptors in cultured rat cerebellar granule neurons and involvement in glutamate-mediated toxicity. J Biochem Toxicol 1996 11:217-226.
44. Haberecht MF, Mitchell CK, Lo GJ and Redburn DA N-methyl-D-aspartate-mediated glutamate toxicity in the developing rabbit retina. J Neurosci Res 1997 47:416-426.