Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis
Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis
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DOI：
10.1073/pnas.1213960109
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发表时间：
2012-10-16
影响因子：
11.1
通讯作者：
Pieper, Andrew A.
中科院分区：
文献类型：
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作者：
Tesla, Rachel;Wolf, Hamilton Parker;Pieper, Andrew A.
我们先前报道了P7 C3的发现，P7 C3是一种氨丙基咔唑，在海马齿状回的新生神经前体细胞中具有前神经发生和神经保护特性。我们还发现，在该体内筛选测定中具有功效的化学物质在暴露于神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（帕金森病的小鼠模型）后也保护黑质的多巴胺能神经元。在这里，我们提供的证据表明，P7 C3的活性类似物，被称为P7 C3 A20，保护腹角脊髓运动神经元细胞死亡的G93 A-SOD 1突变型小鼠模型的肌萎缩侧索硬化症（ALS）。P7 C3 A20在疾病发作时给药时在该模型中是有效的，并且在行走步态测定和加速旋转杆试验中，防止细胞死亡与运动功能的保留相关。该系列的原型成员P7 C3在给药开始时间显著早于预期症状发作时间时延迟G93 A-SOD 1小鼠的疾病进展。Dimebon是一种抗组胺药，其前神经原性和神经保护功效显著弱于P7 C3，在该ALS模型中没有保护作用。我们认为P7 C3和P7 C3 A20所代表的化学支架可能为发现和优化治疗ALS的药物提供基础。
We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS.