Motor neuron dysfunction in a mouse model of ALS: Gender-dependent effect of P2X7 antagonism
Motor neuron dysfunction in a mouse model of ALS: Gender-dependent effect of P2X7 antagonism
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DOI：
10.1016/j.tox.2013.04.004
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发表时间：
2013-09-06
期刊：
影响因子：
4.5
通讯作者：
Marcoli, Manuela
中科院分区：
文献类型：
--
作者：
Cervetto, Chiara;Frattaroli, Daniela;Marcoli, Manuela
肌萎缩侧索硬化症（ALS）是一种神经退行性进行性疾病，目前无法治疗，其特征是选择性运动神经元变性; ALS的发病率和患病率在男性中高于女性。虽然一些重要的机制，可能有助于运动神经元的死亡已被确定，疾病的病理生理机制仍然不确定。特别是，性别在ALS中的作用以及治疗是否应该考虑性二型性的潜在机制仍然只有部分了解。最近，据报道，ATP的P2 X7受体在运动神经元疾病中显示出神经毒性潜力，并且该受体的拮抗作用已被认为有助于这些疾病。研究具有超氧化物歧化酶1基因突变的转基因小鼠，广泛用作ALS模型，可以更好地理解致病机制和对运动神经元的毒性，也可能有助于理解ALS的治疗是否应该考虑性别二型性。这项工作的目的是（I）调查ALS标准模型中疾病进展的性别依赖性-（2）评估P2 X7受体拮抗剂治疗是否应考虑性别二型性。我们评估了性别是否影响过表达突变型超氧化物歧化酶1的小鼠的病程、运动能力、体重减轻和寿命。我们通过旋转棒和握力测试来测量运动障碍、运动强度和协调性。此外，我们评估了用P2 X7受体拮抗剂Brilliant Blue G（一种可以穿过血脑屏障、具有低毒性并且在神经退行性疾病的动物模型中表现出治疗效果的染料）治疗是否对雄性和雌性ALS小鼠的疾病进展产生影响。我们发现（1）发病和疾病进展以及存活取决于性别：（2）P2 X7受体拮抗剂Brilliant Blue G治疗可改善疾病进展。治疗效果是性别依赖性的：改善是男性比女性。总之，我们认为，不仅运动神经元毒性的发病机制，而且药物治疗效果可能取决于性别，性别二型性应考虑在ALS动物模型中的ALS治疗效果的调查。我们的研究结果还指出了P2 X7受体拮抗剂与ALS治疗的潜在相关性，并强调了采用性别特异性方法寻找ALS治疗的重要性。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative progressive currently untreatable disease, characterized by selective motor neuron degeneration; the incidence and prevalence of ALS are greater in men than in women. Although some important mechanisms that might contribute to the death of motor neurons have been identified, the mechanisms underlying disease pathophysiology are still uncertain. In particular, the mechanisms underlying the role of gender in ALS and whether treatments should take into account sexual dimorphism remain only partially understood. Recently, the P2X7 receptor for ATP was reported to display neurotoxic potential in motor neuron disorders, and antagonism of the receptor has been suggested to be helpful in these disorders. Studying transgenic mice with superoxide dismutase 1 gene mutations, widely used as model for ALS, may provide a better understanding of pathogenic mechanisms and of toxicity towards motor neurons, also possibly helping to understand whether treatments for ALS should take into account sexual dimorphism.The aim of the work was (I) investigating on gender-dependence of disease progression in the standard model for ALS - the transgenic mouse bearing superoxide dismutase 1 gene mutations - and (2) assessing if a P2X7 receptor antagonist treatment should take into account sexual dimorphism.We evaluated if gender affect the disease course, the motor performance, the weight loss and the lifespan in mice overexpressing mutant superoxide dismutase 1. We measured motor impairment, motor strength and coordination by rotarod and grip strength testing. Further, we assessed if a treatment with the P2X7 receptor antagonist Brilliant Blue G - a dye that can cross the blood-brain barrier, has low toxicity, and has exhibited therapeutic effects in animal models of neurodegenerative diseases - impact on the disease progression, in male and female ALS mice.We found that (1) the onset and the disease progression, and the survival were dependent on gender: male performed worst than female, lost body weight and died before; (2) treatment with the P2X7 receptor antagonist Brilliant Blue G ameliorated the disease progression. The treatment effect was gender-dependent: amelioration was greater in male than in female.In conclusions, we suggest that not only pathogenetic mechanism of motor neuron toxicity but also the drug treatment effectiveness may depend on gender; sexual dimorphism should be considered when investigating on ALS treatment efficacy in the ALS animal model. Our findings also point on the potential relevance of P2X7 receptor antagonism for ALS treatment, and highlight the importance of adopting a sex-specific approach to searching for treatment of ALS. (C) 2013 Elsevier Ireland Ltd. All rights reserved.