Milbourn Hannah R, Toomey Lillian M, Gavriel Nikolas, Gray Chloe G G, Gough Alexander H, Fehily Brooke, Giacci Marcus K, Fitzgerald Melinda
Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, Perth, Western Australia 6009, Australia.
These authors contributed equally to this article.
Discov Med. 2017 Jun;23(129):361-369.
Following injury to the central nervous system, secondary degeneration is mediated by Ca2+ imbalances and overproduction of reactive oxygen species from mitochondria, and is associated with myelin deficits and loss of function. Preventing intracellular Ca2+ influx at the acute phase of injury is a potential strategy for limiting these deficits and preserving function. The use of single ion channel inhibitors has had little success in attenuating morphological and functional deficits, potentially due to the many pathways by which calcium can traverse the cell membrane. Focus has shifted to the simultaneous administration of a combination of ion channel inhibitors: lomerizine, oxATP, and YM872. The combination has resulted in reductions in oxidative damage, as well as preservation of function and myelin ultrastructure, potentially due to the protection of oligodendrocytes and their progenitors. The use of multiple ion channel inhibitors is promising and suggests a reduction in total intracellular Ca2+ influx is necessary and sufficient for the protection of neurons and glia following neurotrauma. Optimization of treatment timing, inhibitor choice, and method of delivery will be required for translation of this strategy to the clinic.
中枢神经系统损伤后，继发性变性由钙离子失衡和线粒体活性氧过度产生介导，并与髓鞘缺陷和功能丧失有关。在损伤急性期阻止细胞内钙离子内流是限制这些缺陷并保留功能的一种潜在策略。使用单一离子通道抑制剂在减轻形态和功能缺陷方面收效甚微，这可能是由于钙穿过细胞膜的途径众多。研究重点已转向同时联合使用离子通道抑制剂：洛美利嗪、氧化三磷酸腺苷（oxATP）和YM872。这种联合用药已导致氧化损伤减少，以及功能和髓鞘超微结构的保留，这可能是由于对少突胶质细胞及其前体细胞的保护作用。使用多种离子通道抑制剂前景广阔，这表明减少细胞内总钙离子内流对于神经创伤后保护神经元和神经胶质细胞是必要且充分的。要将该策略转化应用于临床，需要优化治疗时机、抑制剂选择和给药方法。
