Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury.
Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury.
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DOI：
10.12688/f1000research.9094.2
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发表时间：
2016-01-01
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影响因子：
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通讯作者：
Habgood, Mark D
中科院分区：
文献类型：
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作者：
Koehn, Liam M;Noor, Natassya M;Habgood, Mark D
脊柱创伤后的组织丢失是双相的，在撞击时最初的机械/出血损伤，随后逐渐向邻近的先前未受影响的组织扩张。限制这种组织损伤的二次扩张的程度有可能保留患者更大的残留脊髓功能。脊髓损伤(SCI)引起的急性组织缺氧激活了酸敏感离子通道1a(ASIC1a)。我们推测，拮抗这一通道对脊髓损伤后的神经保护和功能保护具有一定的作用。我们发现，全身应用蜘蛛毒肽PcTx1，一种选择性的ASIC1a抑制剂，可以改善成年SD大鼠胸部脊髓损伤后的运动功能。功能改善的程度与参与后肢运动功能的下行白质束的组织保存程度相关。转录分析表明，PcTx1诱导的脊髓组织保存并不是细胞凋亡减少的结果，也没有证据表明参与内源性或外源性凋亡途径的关键基因下调。我们还证明，对于10 kDa以下的化合物，创伤导致的血脊髓屏障功能的破坏在损伤后至少持续4天，而对于更大的分子，屏障功能在几个小时内恢复。这种暂时的屏障功能丧失提供了一个“治疗窗口”，通过这个窗口，全身用药可以不受限制地进入创伤部位及其周围的脊柱组织。综上所述，我们的数据提供了证据支持使用ASIC1a抑制剂作为脊髓损伤的治疗方法。这项研究还强调了客观地对早期损伤的功能严重程度进行分级的重要性(即使使用标准化的撞击)，并描述了一种基于后肢功能的简单评分系统，可以在未来的研究中采用。
Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a " treatment window" through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies.