Hu Hui-Jie, Song Mingke
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Stroke Cerebrovasc Dis. 2017 Dec;26(12):2706-2719. doi: 10.1016/j.jstrokecerebrovasdis.2017.09.011. Epub 2017 Oct 18.
Stroke is a leading cause of long-term disability. All neuroprotectants targeting excitotoxicity have failed to become stroke medications. In order to explore and identify new therapeutic targets for stroke, we here reviewed present studies of ionic transporters and channels that are involved in ischemic brain damage.
We surveyed recent literature from animal experiments and clinical reports in the databases of PubMed and Elsevier ScienceDirect to analyze ionic mechanisms underlying ischemic cell damage and suggest promising ideas for stroke therapy.
Dysfunction of ionic transporters and disrupted ionic homeostasis are most early changes that underlie ischemic brain injury, thus receiving sustained attention in translational stroke research. The Na/K-ATPase, Na/Ca Exchanger, ionotropic glutamate receptor, acid-sensing ion channels (ASICs), sulfonylurea receptor isoform 1 (SUR1)-regulated NC channels, and transient receptor potential (TRP) channels are critically involved in ischemia-induced cellular degenerating processes such as cytotoxic edema, excitotoxicity, necrosis, apoptosis, and autophagic cell death. Some ionic transporters/channels also act as signalosomes to regulate cell death signaling. For acute stroke treatment, glutamate-mediated excitotoxicity must be interfered within 2 hours after stroke. The SUR1-regulated NC channels, Na/K-ATPase, ASICs, and TRP channels have a much longer therapeutic window, providing new therapeutic targets for developing feasible pharmacological treatments toward acute ischemic stroke.
The next generation of stroke therapy can apply a polypharmacology strategy for which drugs are designed to target multiple ion transporters/channels or their interaction with neurotoxic signaling pathways. But a successful translation of neuroprotectants relies on in-depth analyses of cell death mechanisms and suitable animal models resembling human stroke.
中风是导致长期残疾的主要原因。所有针对兴奋性毒性的神经保护剂都未能成为中风治疗药物。为了探索和确定中风的新治疗靶点，我们在此回顾了目前关于参与缺血性脑损伤的离子转运体和通道的研究。
我们在PubMed和Elsevier ScienceDirect数据库中调查了近期动物实验和临床报告的文献，以分析缺血性细胞损伤的离子机制，并提出中风治疗的有前景的思路。
离子转运体功能障碍和离子稳态破坏是缺血性脑损伤的最早变化，因此在转化性中风研究中一直受到持续关注。钠钾ATP酶、钠钙交换体、离子型谷氨酸受体、酸敏感离子通道（ASICs）、磺脲类受体亚型1（SUR1）调节的NC通道和瞬时受体电位（TRP）通道在缺血诱导的细胞退化过程中起关键作用，如细胞毒性水肿、兴奋性毒性、坏死、凋亡和自噬性细胞死亡。一些离子转运体/通道还作为信号体调节细胞死亡信号。对于急性中风治疗，必须在中风后2小时内干预谷氨酸介导的兴奋性毒性。SUR1调节的NC通道、钠钾ATP酶、ASICs和TRP通道具有更长的治疗窗口，为开发针对急性缺血性中风的可行药物治疗提供了新的治疗靶点。
下一代中风治疗可以应用多药理学策略，设计药物靶向多种离子转运体/通道或它们与神经毒性信号通路的相互作用。但是神经保护剂的成功转化依赖于对细胞死亡机制的深入分析和类似于人类中风的合适动物模型。
