The lack of effect of specific overexpression of IGF-1 in the central nervous system or skeletal muscle on pathophysiology in the G93A SOD-1 mouse model of ALS
The lack of effect of specific overexpression of IGF-1 in the central nervous system or skeletal muscle on pathophysiology in the G93A SOD-1 mouse model of ALS
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DOI：
10.1016/j.expneurol.2007.05.016
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发表时间：
2007-09-01
影响因子：
5.3
通讯作者：
Delbono, Osvaldo
中科院分区：
文献类型：
--
作者：
Messi, Maria Laura;Clark, Heather M.;Delbono, Osvaldo
胰岛素样生长因子1（IGF-1）预防与肌萎缩侧索硬化（ALS）相关的病理生理学的能力目前正在用动物模型和患者的临床试验中探索。在ALS的SOD-1小鼠模型和一项临床试验中，多项研究报告了IGF-1在减少运动神经元死亡、延迟运动能力下降和延长寿命方面的积极作用。然而，第二项临床试验没有产生积极的结果，这对IGF-1的治疗效果提出了质疑。为了研究骨骼肌或中枢神经系统中特异性和持续的IGF-1表达对运动表现、寿命和运动神经元存活的影响，将人IGF-1转基因小鼠与ALS的G93 A SOD-1突变体模型杂交。在SOD+/IGF-1+和SOD+/IGF-1-杂交小鼠之间，未发现运动性能下降、寿命或脊髓运动神经元存活的发生有显著差异。通过放射免疫测定法测量的IGF-1浓度水平被发现在IGF-1转基因杂交小鼠的中枢神经系统（CNS）和骨骼肌中在整个生命过程中高度增加。此外，与CNS IGF-1转基因小鼠杂交的SOD+小鼠的CNS重量增加表明，即使在疾病完全发展后，IGF-1过表达仍具有生物活性。总之，这些结果提出了关于IGF-1的治疗价值的问题，并表明需要进一步的研究来检查IGF-1给药方法与其潜在治疗价值之间的关系。(c)2007年爱思唯尔公司All rights reserved.
The ability of insulin like growth factor 1 (IGF-1) to prevent the pathophysiology associated with amyotrophic lateral sclerosis (ALS) is currently being explored with animal models and in clinical trials with patients. Several studies have reported positive effects of IGF-1 in reducing motor neuron death, delaying the onset of motor performance decline, and increasing life span, in SOD-1 mouse models of ALS and in one clinical trial. However, a second clinical trial produced no positive results raising questions about the therapeutic efficacy of IGF-1. To investigate the effect of specific and sustained IGF-1 expression in skeletal muscle or central nervous system on motor performance, life span, and motor neuron survival, human-IGF-1 transgenic mice were crossed with the G93A SOD-1 mutant model of ALS. No significant differences were found in onset of motor performance decline, life span, or motor neuron survival in the spinal cord, between SOD+/IGF-1+ and SOD+/IGF-1-hybrid mice. IGF-1 concentration levels, measured by radioinummoassay, were found to be highly increased throughout life in the central nervous system (CNS) and skeletal muscle of IGF-1 transgenic hybrid mice. Additionally, increased CNS weight in SOD+ mice crossbred with CNS IGF-1 transgenic mice demonstrates that IGF-1 overexpression is biologically active even after the disease is fully developed. Taken together, these results raise questions concerning the therapeutic value of IGF-1 and indicate that further studies are needed to examine the relationship between methods of IGF-1 administration and its potential therapeutic value. (c) 2007 Elsevier Inc. All rights reserved.