Pharmacologic evaluation of protective efficacy of caspase inhibitor, diazoxide for spinal cord protection using aspartate segmental infusion model. -Strategy against paraplegia by reducing mitochondrial-dependent apoptotic pathway

使用天冬氨酸节段输注模型评价半胱天冬酶抑制剂、二氮嗪对脊髓保护的保护功效。

• 批准号: 14571276
• 负责人: SHIMIZU Hideyuki
• 金额: $ 1.86万
• 依托单位: KEIO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571276/
• 关键词: Aspartate; Delayed onset paraplegia; Diazoxide; Caspase inhibitor; NMDA; Experimental model; Spinal cord protection; Aspartate segmental infusion model; Amyotrophic lateral sclerosis; Caspase inhibitor; AMPA; kainate受容体; 胸腹部大動脈瘤; 対麻痺

We evaluated the protective effects of caspase inhibitor, diazoxide on spinal cord neurons using segmental aspartate infusion model under brief ischemia in vivo. New Zealand white rabbits underwent an infrarenal aortic isolation. Group A animals(n=7) received intravenous pretreatment of caspase inhibitor, diazoxide (4mg/kg). Group B animals(n=7) received pretreatment of NMDA antagonist, MK-801(6mg/kg) after the pretreatment similar to group A. Group C animals (n=7) received oral medication of riluzole(100mg/kg/day) preoperatively for ten days adding the pretreatment similar to group A. Group D animals(n=7) received viehcles only as a control of group A. Animals received segmental aspartate(30 mM) infusion for 10 minutes at a rate of 2ml/min. Neurologic status was scored at 12,24 and 48 hours after surgery using Tarlov score. Neurologic status was 3.8±0.9 in group A, 3.4±0.6 in group B, 4.0±0.6 in group C, 0.8±0.6 in group D respectively. Animals in group A showed significantly better neurologic recovery compared with group D (p<0.05). There was no significant difference between the functional scores of group A, group Band groupC respectively. Sections from group D exhibited severe gray matter necrosis in ventral horn. In contrast, group A, group B and group C exhibited mild neuronal change with eosinophilic changes. Diazoxide might ameliorate the spinal cord injury induced by segmental aspartate infusion combined with brief ischemia. Pharmacologic strategy using caspase inhibitor, might be a promising strategy against delayed onset paraplegia associated with aortic surgery reducing aspartate excitotoxicity.

采用节段性天冬氨酸灌流模型，观察半胱氨酸天冬氨酸氨基转移酶抑制剂二氮嗪对脊髓神经元短暂缺血的保护作用。新西兰大白兔接受肾下主动脉隔离手术。A组(n=7)静脉注射半胱氨酸天冬氨酸氨基转移酶抑制剂二氮嗪(4 mg/kg)。B组(n=7)在与A组相似的基础上给予NMDA拮抗剂MK-801(6 mg/kg)预处理。C组(n=7)术前口服利鲁唑(100 mg/kg/d)，连续10天。D组(n=7)仅给予A组作为对照。分别于术后12、24、48小时用Tarlov评分对神经功能状态进行评分。神经功能评分A组3.8±0.9，B组3.4±0.6，C组4.0±0.6，D组0.8±0.6。A组动物神经功能恢复情况明显好于D组(p&lt；0.05)。A组、B组、C组功能评分差异无统计学意义。D组腹角灰质严重坏死。而A组、B组和C组则表现为轻度神经元改变，并伴有嗜酸性改变。二氮嗪可减轻节段性门冬氨酸注射合并短暂缺血所致的脊髓损伤。使用半胱氨酸天冬氨酸氨基转移酶抑制剂的药物策略可能是一种有前景的策略，可用于治疗与主动脉手术相关的延迟性截瘫，减少天冬氨酸的兴奋毒性。

项目成果

Cho Y, Ueda T, Mori A et al.: "Neuroprotective effects of N-methyl-D-asparatate Receptor Antagonist on Asparatate Induced Neurotoxicity in the Spinal Cord in vivo"Jpn J Thoracic Surg.. 51(10). 500-505 (2003)

Cho Y、Ueda T、Mori A 等：“N-甲基-D-天冬氨酸受体拮抗剂对体内天冬氨酸诱导的脊髓神经毒性的神经保护作用”Jpn J Thoracic Surg. 51(10)。