Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University, Chongqing, China.
Ann Surg. 2011 Aug;254(2):353-62. doi: 10.1097/SLA.0b013e31822645b4.
To determine the cellular and molecular mechanisms by which acid-sensing ion channel 1a (ASIC1a) plays its role in the secondary injury after traumatic spinal cord injury (SCI), and validate the neuroprotective effect of ASIC1a suppression in SCI model in vivo.
Secondary damage after traumatic SCI contributes to the exacerbation of cellular insult and thereby contributes to spinal cord dysfunction. However, the underlying mechanisms remain largely unknown. Acidosis is commonly involved in the secondary injury process after the injury of central nervous system, but whether ASIC1a is involved in secondary injury after SCI is unclear.
Male Sprague-Dawley rats were subjected to spinal contusion using a weight-drop injury approach. Western blotting and immunofluorescence assays were used to observe the change of ASIC1a expression after SCI. The TUNEL staining in vivo as well as the cell viability and death assays in spinal neuronal culture were employed to assess the role of ASIC1a in the secondary spinal neuronal injury. The electrophysiological recording and Ca(2+) imaging were performed to reveal the possible underlying mechanism. The antagonists and antisense oligonucleotide for ASIC1a, lesion volume assessment assay and behavior test were used to estimate the therapeutic effect of ASIC1a on SCI.
We show that ASIC1a expression is markedly increased in the peri-injury zone after traumatic SCI. Consistent with the change of ASIC1a expression in injured spinal neurons, both ASIC1a-mediated whole-cell currents and ASIC1a-mediated Ca(2+) entry are significantly enhanced after injury. We also show that increased activity of ASIC1a contributes to SCI-induced neuronal death. Importantly, our results indicate that down-regulation of ASIC1a by antagonists or antisense oligonucleotide reduces tissue damage and promotes the recovery of neurological function after SCI.
This study reveals a cellular and molecular mechanism by which ASIC1a is involved in the secondary damage process after traumatic SCI. Our results suggest that blockade of Ca(2+) -permeable ASIC1a may be a potential neuroprotection strategy for the treatment of SCI patients.
确定酸感应离子通道 1a（ASIC1a）在创伤性脊髓损伤（SCI）后继发性损伤中发挥作用的细胞和分子机制，并验证 ASIC1a 抑制在体内 SCI 模型中的神经保护作用。
创伤性 SCI 后的继发性损伤导致细胞损伤加剧，从而导致脊髓功能障碍。然而，其潜在机制在很大程度上仍不清楚。酸中毒通常参与中枢神经系统损伤后的继发性损伤过程，但 ASIC1a 是否参与 SCI 后的继发性损伤尚不清楚。
雄性 Sprague-Dawley 大鼠采用重物坠落损伤法进行脊髓挫伤。Western blot 和免疫荧光检测用于观察 SCI 后 ASIC1a 表达的变化。体内 TUNEL 染色以及脊髓神经元培养中的细胞活力和死亡检测用于评估 ASIC1a 在继发性脊髓神经元损伤中的作用。电生理记录和 Ca(2+)成像用于揭示潜在的机制。ASIC1a 的拮抗剂和反义寡核苷酸、损伤体积评估测定和行为测试用于评估 ASIC1a 对 SCI 的治疗效果。
我们发现，ASIC1a 在创伤性 SCI 后的损伤区周围表达明显增加。与损伤脊髓神经元中 ASIC1a 表达的变化一致，损伤后 ASIC1a 介导的全细胞电流和 ASIC1a 介导的 Ca(2+)内流均显著增强。我们还发现，ASIC1a 活性的增加导致 SCI 诱导的神经元死亡。重要的是，我们的结果表明，通过拮抗剂或反义寡核苷酸下调 ASIC1a 可减少组织损伤并促进 SCI 后神经功能的恢复。
本研究揭示了 ASIC1a 参与创伤性 SCI 后继发性损伤的细胞和分子机制。我们的结果表明，阻断 Ca(2+)通透性 ASIC1a 可能是治疗 SCI 患者的一种潜在神经保护策略。
