Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride
Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride
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DOI：
10.1093/brain/aws325
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发表时间：
2013-01-01
期刊：
影响因子：
14.5
通讯作者：
Palace, Jacqueline
中科院分区：
文献类型：
--
作者：
Arun, Tarunya;Tomassini, Valentina;Palace, Jacqueline
神经退行性变是多发性硬化症永久性残疾的主要原因。目前的免疫调节治疗对神经退行性变的影响是不够的。因此，直接神经保护和骨髓保护仍然是重要的治疗目标。靶向酸敏感离子通道1（由ASIC1基因编码），这有助于有害的Na+和Ca2+的过度细胞内积累，并在急性多发性硬化病变中过度表达，似乎是一个可行的策略，以限制细胞损伤，神经退行性变的基板。虽然通过阿米洛利（目前被许可用于高血压和充血性心力衰竭的保钾利尿剂）阻断ASIC1在多发性硬化症的实验模型中显示出神经保护和骨髓保护作用，但这种策略尚未在多发性硬化症患者中进行测试。在这项转化研究中，我们测试了阿米洛利对原发性进行性多发性硬化患者的神经保护作用。首先，我们评估了进行性多发性硬化症患者死后慢性脑病变中ASIC1的表达，以确定神经保护的靶过程。第二，我们使用神经变性的磁共振成像标记物作为神经保护的结果指标，在14例原发性进展型多发性硬化症患者的队列中测试了阿米洛利的神经保护作用。原发性进展型多发性硬化患者在阿米洛利治疗前（治疗前阶段）和治疗期间（治疗阶段）进行了为期3年的系列磁共振成像扫描。全脑体积和组织完整性采用高分辨率T1加权和扩散张量成像测量。在进行性多发性硬化患者的慢性脑病变中，我们证实了轴突中ASIC1表达增加，并与慢性非活动性病变中的损伤标记物相关。在原发性进展型多发性硬化患者中，我们观察到治疗期间全脑体积的标准化年速率与治疗前相比显著降低（P = 0.018，校正）。与这种减少相一致，我们发现在治疗阶段，主要临床相关的白色物质（胼胝体和皮质脊髓束）和深部灰质（丘脑）结构内组织损伤的扩散指数变化显著降低（P = 0.02，校正）。我们的研究结果扩展了ASIC 1对多发性硬化症神经退行性变的贡献的证据，并表明阿米洛利可能对进行性多发性硬化症患者产生神经保护作用。这项初步研究是第一个针对ASIC1神经保护的转化研究，并支持未来的随机对照试验，测量多发性硬化患者的阿米洛利神经保护。
Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na+ and Ca2+ and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T-1-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, we showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis.