人类RAMP1过表达小鼠对运动敏感的偏头痛治疗具有抗性:前庭偏头痛小鼠模型。

Shafaqat M Rahman, Linda Guo, Carissa Minarovich, Laura Moon, Anna Guo, Anne E Luebke
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引用次数: 0

摘要

背景:运动引起的恶心增强和静态失衡增加都是偏头痛,尤其是前庭偏头痛(VM)的症状。在小鼠模型nestin/hRAMP1中研究了运动诱导的恶心和静态失衡,CNS中表达升高的人类RAMP1水平,从而增强神经系统中的CGRP信号传导。方法:采用运动诱导的体温调节和体位压力中心(CoP)等行为替代方法评估运动敏感性。结果:尾部血管舒张分析显示,与对照组小鼠相比,该模型对低剂量CGRP的敏感性增加。此外,与野生型小鼠相比,nestin/hRAMP1小鼠在姿势摇摆方面表现出更高的动态范围,并且在nestin/hRAMP1雄性小鼠中观察到的摇摆增加,而在雄性同伴对照组中不存在。偏头痛阻滞剂实验的结果很难解释,但数据表明,olgegetant不能逆转cgrp诱导的nestin/hRAMP1小鼠的改变,而rizatriptan对nestin/hRAMP1和对照小鼠无效。结果表明,hRAMP1的过表达导致内源性CGRP信号的升高。结果还表明,在这种CGRP过敏小鼠模型中,奥格孕酮和利扎曲坦对减少CGRP引发的恶心和摇摆无效。结论:本研究提示CGRP过敏可能是前庭偏头痛难治性病例的小鼠模型。试验注册:NA。
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Human RAMP1 overexpressing mice are resistant to migraine therapies for motion sensitivity.

Both enhanced motion-induced nausea and increased static imbalance are observed symptoms in migraine and especially vestibular migraine (VM). Motion-induced nausea and static imbalance were investigated in a mouse model, nestin/hRAMP1, expressing elevated levels of human RAMP1 which enhances CGRP signaling in the nervous system, and compared to non-affected littermate controls. Behavioral surrogates such as the motion- induced thermoregulation and postural sway center of pressure (CoP) assays were used to assess motion sensitivity. Nausea readouts revealed that the nestin/hRAMP1 mouse exhibit an increased sensitivity to CGRP's effects at lower doses compared to unaffected controls. In addition, the nestin/hRAMP1 mice exhibit a higher dynamic range in postural sway than their wildtype counterparts, along with increased sway observed in nestin/hRAMP1 male mice that was not present in male unaffected controls. Results from migraine blocker experiments were challenging to interpret, but the data suggests that olcegepant is incapable of reversing CGRP-induced or endogenous alterations in the nestin/hRAMP1 mice, while rizatriptan was ineffective in both the nestin/hRAMP1 and control mice. The results indicate that overexpression of hRAMP1 leads to heightened endogenous CGRP signaling. Results also suggest that both olcegepant and rizatriptan are ineffective in reducing nausea and sway in this hypersensitive CGRP mouse model. This study suggests that the hypersensitive nestin/hRAMP1 mouse may serve as a model for difficult to treat cases of migraine that exhibit increased motion sensitivity.

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