Lee Lillian L, Galo Ethel, Lyeth Bruce G, Muizelaar J Paul, Berman Robert F
Department of Neurological Surgery, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Exp Neurol. 2004 Nov;190(1):70-8. doi: 10.1016/j.expneurol.2004.07.003.
Overload of intracellular calcium (Ca(2+)) following traumatic brain injury (TBI) has been implicated in the pathogenesis of neuronal injury and death. Voltage-gated calcium channels (VGCCs) provide one of the major sources of Ca(2+) entry into cells. Therefore, the potential neuroprotective activity of SNX-185, a specific N-type VGCC blocker, was tested in rats using the lateral fluid percussion (LFP) model of TBI. SNX-185 (50, 100, or 200 pmol) or vehicle was injected 5 min after injury into the CA2-3 subregion of the hippocampus ipsilateral to TBI. Acute neuronal degeneration was visualized in brain sections 24 h postinjury using the histofluorescent marker Fluoro-Jade (FJ), and the number of surviving neurons in the CA2-3 subregion of the hippocampus 42 days after injury was determined stereologically. Behavioral outcome after TBI and drug treatment was assessed in the beam walk test and Morris water maze. Direct injection of SNX-185 into the CA2-3 region of the hippocampus reduced neuronal injury 24 h after TBI and increased neuronal survival at 42 days at each of the three drug concentrations. Behavioral outcome in both the beam walk and Morris water maze were also improved by SNX-185, with 100 and 200 pmol, but not 50 pmol SNX-185 providing neuroprotection. These data support previous studies demonstrating substantial neuroprotection after TBI by treatment with N-type VGCC blockers.
创伤性脑损伤（TBI）后细胞内钙（Ca(2+)）超载与神经元损伤和死亡的发病机制有关。电压门控钙通道（VGCCs）是Ca(2+)进入细胞的主要来源之一。因此，使用TBI的侧方流体冲击（LFP）模型在大鼠中测试了特异性N型VGCC阻滞剂SNX-185的潜在神经保护活性。在TBI损伤后5分钟，将SNX-185（50、100或200 pmol）或溶剂注射到TBI同侧海马体的CA2-3亚区域。使用组织荧光标记物荧光玉（FJ）在损伤后24小时观察脑切片中的急性神经元变性，并通过立体学方法确定损伤后42天海马体CA2-3亚区域存活神经元的数量。在光束行走试验和莫里斯水迷宫中评估TBI和药物治疗后的行为结果。将SNX-185直接注射到海马体的CA2-3区域可减少TBI后24小时的神经元损伤，并在三个药物浓度下均增加42天时的神经元存活率。SNX-185还改善了光束行走和莫里斯水迷宫中的行为结果，100和200 pmol的SNX-185具有神经保护作用，但50 pmol的SNX-185没有。这些数据支持了先前的研究，即使用N型VGCC阻滞剂治疗TBI后具有显著的神经保护作用。
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