Genetic transfer of the wobbler gene to a C57BL/6J X NZB hybrid stock: Natural history of the motor neuron disease and response to CNTF and BDNF cotreatment
Genetic transfer of the wobbler gene to a C57BL/6J X NZB hybrid stock: Natural history of the motor neuron disease and response to CNTF and BDNF cotreatment
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DOI：
10.1006/exnr.1997.6643
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发表时间：
1997-11-01
影响因子：
5.3
通讯作者：
Mitsumoto, H
中科院分区：
文献类型：
--
作者：
Ishiyama, T;Klinkosz, B;Mitsumoto, H
直到最近，摇摆小鼠 (wr/wr) 运动神经元疾病 (MND) 的临床前诊断仍是不可能的。然而，随着新型杂交小鼠 C57BL/6J x 新西兰黑 (B6NZB)-wr/wr 小鼠的开发，聚合酶链反应 (PCR) 可用于建立临床前诊断。我们比较了杂交 B6NZB-wr/wr 和同系 C57BL/6j-wr/wr 小鼠 MND 的临床和组织学特征以及神经营养因子联合治疗的效果。从 2 周到 8 周，每周对体重、握力、跑步速度、爪子位置和行走方式进行临床评估（n = 10，B6NZB-wr/wr；n = 15，C57BL/6j-wr/wr），分析存活率（n = 7，每个品系）以及 C5 和 C6 脊髓运动神经元形态和腹根组织测定（n = 7，每个品系）。对于联合治疗，8 只 B6NZB-wr/wr 和 7 只 C57BL/6J-wr/wr 小鼠每隔几天接受皮下睫状神经营养因子 (1 mg/kg) 和脑源性神经营养因子 (5 mg/kg)，每周 6 天，持续 4 周。 3周龄时，B6NZB-wr/wr 小鼠与 C57BL/6J-wr/wr 小鼠的区别在于更异常的爪位置 (P < 0.01) 和行走模式 (P < 0.05) 以及较低的握力 (P < 0.001) 和跑步速度 (P < 0.001)。 3周后，B6NZB-wr/wr小鼠的变化继续更大。尽管B6NZB-wr/wr小鼠在疾病早期受到更严重的影响，但它们的存活率与C57BL/6J-wr/wr小鼠相当，两种品系的前角细胞空泡变性和有髓纤维组织测定相似。两组对 CNTF/BDNF 联合治疗的临床反应均显着，但 B6NZB-wr/wr 小鼠的临床反应较弱。因此，杂交 B6NZB-wr/wr 小鼠具有更严重的临床表型，并为研究症状前运动神经元变性的机制和人类 MND 治疗药物的效果提供了独特的机会。 (C) 1997 年学术出版社。
Preclinical diagnosis of motor neuron disease (MND) in the wobbler mouse (wr/wr) has been impossible until recently. However, with the development of a new hybrid, the C57BL/6J x New Zealand Black (B6NZB)-wr/wr mouse, the polymerase chain reaction (PCR) can be used to establish the preclinical diagnosis. We compared the clinical and histological features of MND and the effects of neurotrophic factor cotreatment between the hybrid B6NZB-wr/wr and the congenic C57BL/6j-wr/wr mice. Clinical assessments of body weight, grip strength, running speed, paw position, and walking pattern were made weekly from age 2 weeks through 8 weeks (n = 10, B6NZB-wr/wr; n = 15, C57BL/6j-wr/wr), Survival was analyzed (n = 7, each strain) as was C5 and C6 spinal cord motoneuron morphology and ventral root histometry (n = 7, each strain). For cotreatment, 8 B6NZB-wr/wr and 7 C57BL/6J-wr/wr mice received subcutaneous ciliary neurotrophic factor (1 mg/kg) and brain-derived neurotrophic factor (5 mg/kg) on alternate days, 6 days/week for 4 weeks. B6NZB-wr/wr mice could be distinguished from C57BL/6J-wr/wr mice at age 3 weeks by a more abnormal paw position (P < 0.01) and walking pattern (P < 0.05) and lower grip strength (P < 0.001) and running speed (P < 0.001). After 3 weeks, the changes continued to be greater in B6NZB-wr/wr mice. Although B6NZB-wr/wr mice were more severely affected early in the disease, their survival was comparable to C57BL/6J-wr/wr mice, Anterior horn cell vacuolar degeneration and myelinated fiber histometry were similar in both strains. The clinical response to CNTF/BDNF cotreatment was marked in both groups although it was weaker in B6NZB-wr/wr mice. Thus, the hybrid B6NZB-wr/wr mice have a more severe clinical phenotype and offer a unique opportunity to study the mechanisms of presymptomatic motor neuron degeneration and the effects of therapeutic agents for human MND. (C) 1997 Academic Press.