Molecular pathomechanism of amyotrophic lateral sclerosis

肌萎缩侧索硬化症的分子病理机制

• 批准号: 11470145
• 负责人: SHIMOHAMA Shon
• 金额: $ 8.64万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470145/
• 关键词: Amyotrophic lateral sclerosis (ALS); motor neuron; cell death; estradiol; cyclic GMP; protection; oxidative stress; ALS; ホスホジエステラーゼ(PPE); CGMP; グルタミン酸; アミノフィリン; アイソザイム; 家族性筋萎縮性側索硬化症; Cu; Zn superoxide dismutase(SOD-I); グリア; 野生株; 変異SOD-1

In the present study, we demonstrated that 17β-estradiol and its biologically inactive stereoisomer, 17α-estradiol, prevented glutamate- and nitric oxide-induced selective motor neuronal death observed in primary cultures of the rat spinal cord. The dose of estradiols required for motor neuron protection was greatly reduced by co-administration with glutathione. The results of this study shows that estradiol protects spinal motor neurons from excitotoxic insults in vitro, and may have application as a treatment for amyotrophic lateral sclerosis (ALS).We also investigated the effect of cyclic GMP against reactive oxygen species (ROS)-induced toxicity in cultured neurons from embryonic rat spinal cords. Pretreatment with a cGMP analogue for 12-24 hours protected both spinal motor neurons and nonmotor neurons against injury induced by either hydrogen peroxide, or a glutathione depletor, BSO.This protective effect was reversed by coadministration with the cGMP-dependent protein kinase (PKG) inhibitor. Interestingly, when cultures were exposed to BSO for 24 hours to allow irreversible inhibition of glutathione synthesis, 8br-cGMP protected only nonmotor neurons. Our results indicate that cGMP attenuates oxidative injury to cultured spinal neurons, in a mechanism associated with glutathione synthesis.

在本研究中，我们证明了17β-雌二醇及其生物学上无活性的立体异构体17α-雌二醇可预防在大鼠脊髓原代培养物中观察到的谷氨酸和一氧化氮诱导的选择性运动神经元死亡。运动神经元保护所需的雌二醇的剂量通过与谷胱甘肽共同给药而大大降低。本研究的结果表明，雌二醇保护脊髓运动神经元免受兴奋性毒性损伤，并可能作为治疗肌萎缩侧索硬化症（ALS）的应用。我们还研究了环鸟苷酸对活性氧（ROS）诱导的胚胎大鼠脊髓培养神经元毒性的影响。cGMP类似物预处理12-24小时可保护脊髓运动神经元和非运动神经元免受过氧化氢或谷胱甘肽耗竭剂BSO诱导的损伤，这种保护作用可被cGMP依赖性蛋白激酶（PKG）抑制剂逆转。有趣的是，当培养物暴露于BSO 24小时以允许谷胱甘肽合成的不可逆抑制时，8br-cGMP仅保护非运动神经元。我们的研究结果表明，环鸟苷酸减弱氧化损伤培养脊髓神经元，在与谷胱甘肽合成的机制。

项目成果

Shimohama S,Kihara T: "Nicotinic receptor-mediated protection against beta amyloid neurotoxicity"Biolopgical Psychiatry. (in press). (2001)

Shimohama S，Kihara T：“烟碱受体介导的针对β淀粉样蛋白神经毒性的保护”生物精神病学。

Sawada H.et al: "Neuroprotective mechanism of glial cell line-derived neurotrophic factor in mesencephalic neurons"Journal of Neurochemistry. 74. 1175-1184 (2000)

Sawada H.等人：“中脑神经元中胶质细胞系源性神经营养因子的神经保护机制”神经化学杂志。

Nakamizo et al: "Protection of motor neurons by estradiol"Neuroreport. 11. 3493-3497 (2000)

Nakamizo 等人：“雌二醇保护运动神经元”Neuroreport。

Urushitani M, Nakamizo T, Inoue R, Sawada H, Kihara T, Honda K, Akaike A, Shimohama S: "N-methyl-D-aspartate receptor-mediated mitochondrial Ca^<2+> overload in acute excitotoxic motor neurons death : A mechanism distinct from chronic neurotoxicity after

Urushitani M、Nakamizo T、Inoue R、Sawada H、Kihara T、Honda K、Akaike A、Shimohama S：“N-甲基-D-天冬氨酸受体介导的线粒体 Ca^<2> 急性兴奋毒性运动神经元死亡中的过载：A

Kawasaki H.et al.: "Requirement for mitogen-activated protein kinase in cerebellor long term depression"Journal of Biological Chemistry. 274. 13498-13502 (1999)

Kawasaki H.等人：“小脑长期抑郁症中丝裂原激活蛋白激酶的需求”生物化学杂志。