Evaluation of riluzole therapy using the glutamate segmental infusion model. - Development of pharmacologic spinal cord protection for amyotrophic lateral screlosis (ALS) -

使用谷氨酸分段输注模型评估利鲁唑治疗。

• 批准号: 12671327
• 负责人: UEDA Toshihiko
• 金额: $ 1.79万
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671327/
• 关键词: Gulutamate; Amyotrophic lateral screlosis; Rilusole; NBQX; AMPA; kainite receptor; Experimental model; spinal cord protection; Glutamate segmental infusion model; Glutamate neurotoxicity; 脊髄; 実験動物モデル

Amyotrophic lateral screlosis (ALS) is a progressive motor neuron disease for which there is no adequate treatment. The antiglutamate agent riluzole was reported to slow the progression of ALS in clinical prospective controlled study. Using the segmental glutamate infusion model, we evaluated protective effects of riluzole and NBQX, which is an AMPA/kainate antagonist, to spinal cord in vivo. Method; Infrarenal isolation was performed in New Zealand white rabbits (3.5-4.0kg). Group A animals (n=7) were orally treated with riluzole (100mg/kg/day) for ten days before surgery. Group B animals (n=7) were fed without riluzole. Glutamate solution (50mM) was infused to the isolated abdomial aortic segment at a rate of two ml/min for 5 minutes. Group C (n=8) and group D (n=8) animals received riluzole (100mg/kg/day) for ten days. Group E (n=8) animals were fed without riluzole. Group D and group E animals were pretreated with NBQX (4 mg/kg), followed by the infusion of glutamate (50mM) for 5 minutes. Group C animals received vehicle, followed by the glutamate infusion in the same manner. Neurologic status was assessed using the Tarlov system. Results; Neurologic scores in group A, group B were 3.7±1.6 and 0.8±0.6 respectively. Group A animals exhibited better neurologic recovery compared with group B significantly (p<0.05). Neurologic scores in group C, group D, and group E were 3.2±0.6, 4.1±0.5 and 2.3±0.7 respectively. Group D animals exhibited better neurologic recovery compared with group C and group E significantly (p<0.05). Conclusion; Riluzole combined with NBQX can improve spinal cord recovery in the segmental glutamate infusion model.

肌萎缩性侧索硬化症（ALS）是一种进行性运动神经元疾病，目前尚无足够的治疗方法。在临床前瞻性对照研究中，抗谷氨酸药物利鲁唑被报道可以减缓ALS的进展。采用节段性谷氨酸输注模型，我们评估了利鲁唑和NBQX （AMPA/kainate拮抗剂）对脊髓的保护作用。方法;采用3.5 ~ 4.0kg的新西兰大白兔进行肾下分离。A组动物（n=7）术前10 d口服利鲁唑（100mg/kg/天）。B组（n=7）不饲喂利鲁唑。谷氨酸溶液（50mM）以2ml /min的速率注入离体腹主动脉段，持续5分钟。C组（n=8）和D组（n=8）给予利鲁唑（100mg/kg/ D），连用10 D。E组（n=8）不饲喂利鲁唑。D组和E组动物先用NBQX （4 mg/kg）预处理，然后注射谷氨酸（50mM） 5分钟。C组大鼠先给药，再按相同方法灌胃谷氨酸。使用Tarlov系统评估神经系统状态。结果;A组、B组神经学评分分别为3.7±1.6分、0.8±0.6分。A组动物神经功能恢复明显优于B组（p<0.05）。C组、D组、E组神经功能评分分别为3.2±0.6、4.1±0.5、2.3±0.7。D组动物神经功能恢复明显优于C组和E组（p<0.05）。结论;利鲁唑联合NBQX可改善节段性谷氨酸输注模型脊髓恢复。

项目成果

Ueda T, Shimizu H, Ito T, Kashima I., et al.: "Cerebral complicaiton associated with clamping the aorta between the left subclavian artery"The annals of thoracic surgery. 70(5). 1472-1477 (2000)

Ueda T、Shimizu H、Ito T、Kashima I.等人：“与夹闭左锁骨下动脉之间的主动脉相关的脑并发症”胸外科年鉴。

Ueda T, Shimizu H, Mori A, Kashima I, Moro K, Kawada S: "Selective perfusion of segmental arteries in patients undergoing thoracoabdominal aotic Surgery"Ann Thorac Surg. 70 (1). 38-43 (2000)

Ueda T、Shimizu H、Mori A、Kashima I、Moro K、Kawada S：“接受胸腹主动脉手术的患者的节段动脉的选择性灌注”Ann Thorac Surg。

Ueda T, Shimizu H, Moro K., et al.: "Complication associated with clamping the aorta between the left common carotid artery and left subclavian artery"The annals of the thoracic surgery. 70(2). 558-561 (2000)

Ueda T、Shimizu H、Moro K.等人：“与夹闭左颈总动脉和左锁骨下动脉之间的主动脉相关的并发症”胸外科年鉴。

Ueda T, Shimizu H, Ito T, Kashima I et al.: "Cerebral complication associated with selective perfusion of the arch vessels"The annals of thoracic surgery. 70(5). 1472-1477 (2000)

Ueda T、Shimizu H、Ito T、Kashima I 等：“与弓形血管选择性灌注相关的脑并发症”胸外科年鉴。

Cho Y,Ueda T,Mori A.: "Exogenous aspartate neurotoxicity in the spinal cord under metabolic stress in vivo."The Annals of Thoracic Surgery. 70(5). 1496-1500 (2000)

Cho Y，Ueda T，Mori A.：“体内代谢应激下脊髓中的外源性天冬氨酸神经毒性。”胸外科年鉴。