Mechanisms of protectiion by neurotrophins against NO-mediated glutamate neurotoxicity

神经营养素对 NO 介导的谷氨酸神经毒性的保护机制

• 批准号: 09470502
• 负责人: AKAIKE Akinori
• 金额: $ 8.38万
• 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: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470502/
• 关键词: nitric oxide; gulutamate; neuronal death; neuroprotection; cerebral cortex; N-methyl-D-aspartate; neurotrophin; brain-derived neurotrophic factor; 初代培養神経細胞; NMDA受容体

This project is aimed to determine the mechanisms of protective action of neurotrophins against glutamate neurotoxicity in the cerebral cortex by using cortical cultures derived from fetal rats. Brain-derived neurotrophic factor (BDNF) potently prevented NMDA receptor-mediated glutamate neurotoxicity when the cultures were exposed to BDNF for 24 hr prior to glutamate exposure. Protective effect of BDNF was inhibited by an inhibitor of protein synthesis. Those results suggest that de novo synthesis of intracellular proteins is involved in the neuroprotective action of BDNF.BDNF induced tyrosine phosphorylation of its high affinity receptor, TrkB.By contrast, the effect of BDNF was not affected by the addition of antibody for p75, a low affinity neurotrophin receptor. BDNF did not increase ceramide formation. BDNF prevented cytotoxicity induced by a calcium ionophore such as ionomycin and a NO donor such as S-nitrosocysteine. Those findings indicate that BDNF selectively interacts with TrkB to promote de novo synthesis of functional molecules which ameliorate neurotoxicity triggered by free radicals including nitric oxide and superoxide. The results of our project give a new scope for the creation of novel drugs protecting neuronal death in neurodegenerative disorders.

本项目旨在通过胎儿大鼠大脑皮层培养物，探讨神经营养因子对谷氨酸神经毒性的保护作用机制。脑源性神经营养因子（BDNF）在谷氨酸暴露前暴露于BDNF 24小时，可有效预防NMDA受体介导的谷氨酸神经毒性。BDNF的保护作用被一种蛋白质合成抑制剂所抑制。这些结果表明，细胞内蛋白的从头合成参与了BDNF的神经保护作用。BDNF诱导其高亲和力受体TrkB的酪氨酸磷酸化。相比之下，BDNF的作用不受添加p75抗体（一种低亲和力的神经营养因子受体）的影响。BDNF不增加神经酰胺的形成。BDNF可防止钙离子载体（如离子霉素）和NO供体（如s -亚硝基半胱氨酸）诱导的细胞毒性。这些发现表明，BDNF选择性地与TrkB相互作用，促进功能分子的重新合成，从而改善自由基（包括一氧化氮和超氧化物）引发的神经毒性。我们项目的结果为创造保护神经退行性疾病中神经元死亡的新药提供了新的范围。

项目成果

Kaneko, S.et al.: "Differential regulation of N-and Q-type Ca^<2+> channels by cyclic nucleotides and G-proteins." Life Sci.62. 1543-1547 (1998)

Kaneko, S.et al.：“环核苷酸和 G 蛋白对 N 型和 Q 型 Ca^2 通道的差异调节”。

Sawada, H.et al: "Dopamine D_2-type agonists protect mesencepalic neurons from glutamate neurotoxicity : mechanisms of neuroprotective treatment against oxidative stress." Ann.Neurol.44. 110-119 (1998)

Sawada, H.等人：“多巴胺 D_2 型激动剂保护中脑神经元免受谷氨酸神经毒性：针对氧化应激的神经保护治疗机制。”

久米利明 他: "グルタミン酸神経毒性を制御する内在性保護因子" 医学のあゆみ 『ニューロン死を標的とした神経疾患治療薬5』, 4 (1998)

Toshiaki Kume 等：“控制谷氨酸神经毒性的内源性保护因子”医学史“针对神经元死亡的神经系统疾病的治疗”，4 (1998)

Matsubara, K.et al.: "Endogenously occurring beta-carboline in duces parkinsonisum in nonpromate animals : a possible caus ative protoxin in idiopathic parkinson's disease." J.Neurochem.70. 727-735 (1998)

Matsubara, K. 等人：“非原性动物帕金森病中内源性存在的 β-咔啉：一种可能导致特发性帕金森病的原毒素。”

Kaneda, K.et al.: "Apoptotic DNA fragmentation and upregulation of Bax induced by transiet ischemia of the rat retina." Brain Res.815. 11-20 (1998)

Kaneda, K. 等人：“大鼠视网膜短暂缺血诱导的细胞凋亡 DNA 片段化和 Bax 上调。”