Development of factors that prevent secondary neuronal degeneration

预防继发性神经元变性的因素的开发

• 批准号: 11671370
• 负责人: DESAKI Junzo
• 金额: $ 0.96万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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/grant/KAKENHI-PROJECT-11671370/
• 关键词: secondary neuronal degeneration; gerbil; hippocampus; prosaposin-related peptide; apoptosis; Bcl-x_L; passive avoidance experiment; 神経細胞の二次変性; 一過性前脳虚血; インターロイキン3; エリスロポエチン; ジンセノサイドRb_1

The 7-day infusion of a prosaposin-related 18-mer peptide (18-MP) into the lateral ventricle of gerbils starting 2 hours before or just after 3-min forebrain ischemia is known to prevent the occurrence of learning disability and neuronal death in the hippocampal CA1 field. However, it remains to be determined whether or not intracerebroventricular infusion of the 18-MP starting 72 hours after 3-min forebrain ischemia rescues hippocampal CA1 neurons, and the mechanism (s) by which the 18-MP exerts a protective effect on ischemic hippocampal CA1 neurons also remains to be determined. In the first set of the present experiments, gerbils were infused with the 18-MP for 28 days into the lateral ventricle at 72 hours after 3-min forebrain ischemia. 18-MP infusion prevented the occurrence of ischemia-induced learning disability in a dose-dependent manner as revealed by the step-down passive avoidance task. Subsequent light microscopic examinations showed that pyramidal neurons in the CA1 region of the hippocampus were significantly more numerous in gerbils infused with the 18-MP than in those receiving vehicle infusion. In the second set of the present experiments, the 18-MP prevented in vitro neuronal apoptosis or apoptotic neuron death caused by the nitric oxide (NO) donor sodium nitroprusside (SNP) in a concentration-dependent manner. Moreover, the 18-MP (1-10^5 fg/ml) increased the expression of Bcl-x_L, an antiapoptotic Bcl-2 family protein, in cultured neurons. Thus, the present study indicates that the 18-MP prevents secondary neuronal degeneration after ischemia in vivo possibly through an increase in the expression of the antiapoptotic factor, Bcl-x_L.

在沙鼠前脑缺血前2小时或后3分钟开始向其侧脑室输注prosaposin-related 18-mer peptide (18-MP) 7天，可以预防海马CA1区学习障碍和神经元死亡的发生。然而，在3分钟前脑缺血后72小时开始的18-MP脑室内输注是否能拯救海马CA1神经元，以及18-MP对缺血海马CA1神经元的保护作用机制仍有待确定。在本实验的第一组实验中，沙鼠在前脑缺血3 min后72小时向侧脑室注入18-MP，持续28天。降压被动回避任务显示，18-MP输注对缺血性学习障碍的发生具有剂量依赖性。随后的光镜检查显示，输注18-MP的沙鼠海马CA1区的锥体神经元数量明显多于接受载药输注的沙鼠。在本实验的第二组中，18-MP以浓度依赖的方式阻止一氧化氮（NO）供体硝普钠（SNP）引起的体外神经元凋亡或凋亡性神经元死亡。此外，18-MP （1-10^5 fg/ml）增加了Bcl-x_L（抗凋亡Bcl-2家族蛋白）在培养神经元中的表达。因此，本研究表明，18-MP可能通过增加抗凋亡因子Bcl-x_L的表达来防止体内缺血后的继发性神经元变性。

项目成果

Igase K et al.: "An 18-mer peptide fragment of prosaposin ameliorates place navigation disability, cortical infarction, and retrograde thalamic degeneration in rats with focal cerebral ischemia."J Cereb.Blood Flow Metab.. 19. 298-306 (1999)

Igase K 等人：“Prosaposin 的 18 聚体肽片段可改善局灶性脑缺血大鼠的位置导航障碍、皮质梗塞和逆行丘脑变性。”J Cereb.Blood Flow Metab.. 19. 298-306 (1999)

Fujita H et al.: "Differential expressions of glycine transporter 1 and three glutamate transporter mRNAs in the hippocampus of gerbils with transient forebrain ischemia."J.Cereb.Blood Flow Metab.. 19. 604-615 (1999)

Fujita H 等人：“短暂前脑缺血沙鼠海马中甘氨酸转运蛋白 1 和三种谷氨酸转运蛋白 mRNA 的差异表达。”J.Cereb.Blood Flow Metab.. 19. 604-615 (1999)

Yang L et al.: "Improvement of the viability of cultured rat neurons by the non-essential amino acids L-serine and glycine that upregulates expression of the anti-apoptotic gene product Bcl-w."Neuroscience Letters. 295. 97-100 (2000)

Yang L 等人：“通过非必需氨基酸 L-丝氨酸和甘氨酸上调抗凋亡基因产物 Bcl-w 的表达，提高培养的大鼠神经元的活力。”《神经科学快报》。

Nakatsuka H et al.: "Cytochrome c release from mitochondria to the cytosol was suppressed in the ischemia-tolerance-induced hippocampal CA1 region after 5-min forebrain ischemia in gerbils."Neuroscience Letters. 278. 53-56 (2000)

Nakatsuka H 等人：“沙鼠前脑缺血 5 分钟后，在缺血耐受诱导的海马 CA1 区域，细胞色素 c 从线粒体释放到胞浆中受到抑制。”《神经科学快报》。

Nakatsuka H et al.: "Cytochrome c release from mitochondria to the cytosol was suppressed in the ischemia-tolerance-induced hippocampal CA1 region after 5-min forebrain ischemia in gerbils."Neuroscience Letters,. 278. 53-56 (2000)

Nakatsuka H 等人：“沙鼠前脑缺血 5 分钟后，在缺血耐受诱导的海马 CA1 区域，细胞色素 c 从线粒体释放到胞质溶胶中受到抑制。”《神经科学快报》，。