Groeneveld Geert J, van Muiswinkel Freek L, de Leeuw van Weenen Judith, Blauw Hylke, Veldink Jan H, Wokke John H J, van den Berg Leonard H, Bär Peter R
Department of Neurology, Laboratory for Experimental Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Dec;5(4):220-5. doi: 10.1080/14660820410019530.
There is an accumulating body of evidence that apoptosis is involved in the motor neuron death that occurs in ALS, and in the (G93A) mSOD1 transgenic mouse model (mSOD1 mice). CGP 3466B, a tricyclic propargylamine structurally related to (-)-deprenyl, was found to inhibit apoptosis in a wide variety of in vitro and in vivo models. We therefore studied the effect of CGP 3466B in mSOD1 mice.
As the effect of CGP 3466B was previously reported to have a bell-shaped curve, we performed a dose-ranging study. High-copy G93A mSOD1 mice were treated subcutaneously from the age of 50 days until death with four concentrations of CGP 3466B (0.39 microg kg(-1), 3.9 microg kg(-1), 39 microg kg(-1), and 390 microg kg(-1)). Behavioural tests were performed daily to determine disease onset, disease progression and survival. At the age of 110 days, two mice per group were sacrificed for histopathological analysis of the lumbar ventral horn and for semiquantitative analysis of motor neuron number.
We observed no effect on disease onset, disease progression, or survival of the mice. We also did not observe a significant effect on the number of motor neurons due to CGP 3466B.
We conclude that in high-copy G93A mSOD1 mice, chronic subcutaneous treatment with CGP 3466B offers no clinical benefit.
越来越多的证据表明，细胞凋亡参与了肌萎缩侧索硬化症（ALS）以及（G93A）突变型超氧化物歧化酶1（mSOD1）转基因小鼠模型（mSOD1小鼠）中运动神经元的死亡。CGP 3466B是一种与（-）-司来吉兰结构相关的三环炔丙胺，在多种体外和体内模型中被发现可抑制细胞凋亡。因此，我们研究了CGP 3466B对mSOD1小鼠的影响。
由于之前报道CGP 3466B的作用呈钟形曲线，我们进行了剂量范围研究。高拷贝G93A mSOD1小鼠从50日龄开始皮下注射四种浓度的CGP 3466B（0.39μg kg⁻¹、3.9μg kg⁻¹、39μg kg⁻¹和390μg kg⁻¹），直至死亡。每天进行行为测试以确定疾病发作、疾病进展和生存期。在110日龄时，每组处死两只小鼠，用于腰髓腹角的组织病理学分析和运动神经元数量的半定量分析。
我们未观察到对小鼠疾病发作、疾病进展或生存期有影响。我们也未观察到CGP 3466B对运动神经元数量有显著影响。
我们得出结论，在高拷贝G93A mSOD1小鼠中，CGP 3466B的慢性皮下治疗没有临床益处。
