A proposed mechanism for amitriptyline neurotoxicity based on its detergent nature.
A proposed mechanism for amitriptyline neurotoxicity based on its detergent nature.
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DOI：
10.1016/j.taap.2006.08.003
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发表时间：
2006-11
影响因子：
3.8
通讯作者：
N. Kitagawa;M. Oda;I. Nobutaka;H. Satoh;T. Totoki;M. Morimoto
中科院分区：
文献类型：
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作者：
N. Kitagawa;M. Oda;I. Nobutaka;H. Satoh;T. Totoki;M. Morimoto
尽管阿米替林作为一种有效的局部麻醉剂而受到关注，但最近的动物研究表明，它会导致不可逆的神经损伤。我们假设由增溶作用（一种常见的洗涤剂特性）引起的神经膜破坏是阿米替林神经毒性的原因。我们使用两阶段方法来检验我们的假设。首先，我们测定了（1）阿米替林的分子聚集浓度，（2）破坏人工脂质膜的阿米替林浓度和（3）引起溶血的阿米替林浓度。其次，我们将这些水平与通过改变皮肤刺激阈值（CST）对脊髓麻醉大鼠模型进行评估而确定的神经毒性浓度进行了比较。引起分子聚集、模型膜破坏和溶血的阿米替林浓度分别为 0.46%、0.35% 和 0.3%。动物研究表明，阿米替林≥0.3% 时 CST 显着增加，表明存在神经功能损害。由于阿米替林在分子聚集浓度下引起模型膜破坏和溶血，因此增溶作用在人工膜和红细胞的破坏中发挥作用。此外，这些浓度也与引起神经损伤的最低浓度非常一致。因此，虽然需要进行包括组织病理学在内的其他研究来澄清这一观察结果，但阿米替林的神经毒性似乎与其洗涤剂性质有关。
Although amitriptyline has gained attention as a potent local anesthetic, recent animal studies showed that it can cause irreversible neural impairment. We hypothesized that nerve membrane disruption caused by solubilization, a common detergent property, accounted for amitriptyline neurotoxicity. We used a two-phase approach to test our hypothesis. Firstly, we determined (1) the molecular aggregation concentration of amitriptyline, (2) the concentration of amitriptyline that disrupts artificial lipid membranes and (3) the concentration of amitriptyline that causes hemolysis. Secondly, we compared these levels with neurotoxic concentrations determined from assessment in a rat model of spinal anesthesia using changes in cutaneous stimulus threshold (CST). Amitriptyline concentrations that caused molecular aggregation, model membrane disruption and hemolysis were 0.46%, 0.35% and 0.3%, respectively. Animal study showed a significant increase in CST at ≥0.3% of amitriptyline, indicating neurological impairment. Since amitriptyline caused model membrane disruption and hemolysis at the molecular aggregation concentration, solubilization plays a role in the destruction of artificial membranes and erythrocytes. Furthermore, these concentrations are also in good agreement with the minimum concentration causing neurological injury. Therefore, while additional studies, including histopathology, are necessary to clarify this observation, amitriptyline neurotoxicity appears to be associated with its detergent nature.