Calpain inhibitors prevent neuronal cell death and ameliorate motor disturbances after compression-induced spinal cord injury in rats
Calpain inhibitors prevent neuronal cell death and ameliorate motor disturbances after compression-induced spinal cord injury in rats
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DOI：
10.1089/neu.2005.22.398
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发表时间：
2005-03-01
影响因子：
4.2
通讯作者：
Matsui, H
中科院分区：
文献类型：
--
作者：
Arataki, S;Tomizawa, K;Matsui, H
创伤性脊髓损伤(SCI)导致广泛的神经细胞死亡。最近的研究表明，激活的钙蛋白酶介导了中枢神经系统的神经细胞死亡。我们进行了一项研究，以确定Calain是否介导了脊髓损伤后脊髓运动神经元的神经细胞死亡，以及损伤后给予Calain抑制剂N-乙酰-亮氨酸-甲硫氨酸-CHO(ALLm)和Calain抑制剂III(CI III)(MDL28170)是否减少了脊髓损伤大鼠的运动障碍。成年雄性Wistar大鼠在脊髓T12处应用20g质量撞击探头致脊髓损伤20min。按脊髓损伤后每24 h静脉注射0.05~2.5 mg/kg Allm、10 mg/kg CI III或0.1%DMSO作为对照，将大鼠分为3组。脊髓损伤后8小时、24小时和5天，脊髓中的钙蛋白酶被激活，给予Alm可抑制其激活。与单纯DMSO载体相比，ALM还显著减少了脊髓损伤后24小时脊髓损伤后用末端脱氧核苷酸转移酶-尿苷核苷酸末端标记(TUNEL)技术阳性标记的脊髓损伤的运动神经元数量。此外，斜面试验和足迹分析均显示，注射ALLM或CI III的大鼠在4周后的运动活动明显好于仅注射赋形剂的大鼠。这些结果表明，Calain的激活在脊髓损伤后神经细胞的死亡中起着关键作用，Calain抑制剂可能在治疗SCI后的运动障碍方面有好处。
Traumatic spinal cord injury (SCI) results in widespread neuronal cell death. Recent studies have suggested that activated calpain mediates neuronal cell death in the central nervous system. We conducted a study to determine whether calpain mediates neuronal cell death in the motor neurons of the spinal cord after SCI, and whether postinjury administration of the calpain inhibitors N-acetyl-Leu-Leu-Met-CHO (ALLM) and calpain inhibitor III (CI III) (MDL28170) reduces the motor disturbances in rats with a model of SCI. Adult male Wistar rats were subjected to SCI by application of a 20-g weight impactor probe to the spinal cord at T12 for 20 min. The rats were divided into three groups according to whether they were injected intravenously with 0.05-2.5 mg/kg ALLM, 10 mg/kg CI III, or 0.1% DMSO as a control every 24 h for I week after SCI. Calpain was activated in the spinal cord at 8 h, 24 h, and 5 days after SCI, and administration of ALLM inhibited its activation. ALLM, as compared to the DMSO vehicle alone, also significantly reduced the number of motor neurons in spinal-cord lesions that were positively labeled at 24 h after SCI with the terminal deoxynucleotidyl transferase-uridine nucleotide end-labeling (TUNEL) technique. Additionally, both the inclined plane test and footprint analysis showed markedly better motor activity after 4 weeks in rats injected with ALLM or CI III than in rats given vehicle only. These results suggest that activation of calpain plays a critical role in the neuronal cell death that follows SCI, and that calpain inhibitors may have benefit in treating the motor disturbances that follow SCI.