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缺血性中风的治疗靶点前景与方向

Prospects of Therapeutic Target and Directions for Ischemic Stroke.

作者信息

Kim Jung Hak, Kim So Young, Kim Bokyung, Lee Sang Rae, Cha Sang Hoon, Lee Dong Seok, Lee Hong Jun

机构信息

Research Institute, e-biogen Inc., Seoul 07282, Korea.

College of Medicine, Chung-Ang University, Seoul 06974, Korea.

出版信息

Pharmaceuticals (Basel). 2021 Apr 1;14(4):321. doi: 10.3390/ph14040321.

Abstract

Stroke is a serious, adverse neurological event and the third leading cause of death and disability worldwide. Most strokes are caused by a block in cerebral blood flow, resulting in neurological deficits through the death of brain tissue. Recombinant tissue plasminogen activator (rt-PA) is currently the only immediate treatment medication for stroke. The goal of rt-PA administration is to reduce the thrombus and/or embolism via thrombolysis; however, the administration of rt-PA must occur within a very short therapeutic timeframe (3 h to 6 h) after symptom onset. Components of the pathological mechanisms involved in ischemic stroke can be used as potential biomarkers in current treatment. However, none are currently under investigation in clinical trials; thus, further studies investigating biomarkers are needed. After ischemic stroke, microglial cells can be activated and release inflammatory cytokines. These cytokines lead to severe neurotoxicity via the overactivation of microglia in prolonged and lasting insults such as stroke. Thus, the balanced regulation of microglial activation may be necessary for therapy. Stem cell therapy is a promising clinical treatment strategy for ischemic stroke. Stem cells can increase the functional recovery of damaged tissue after post-ischemic stroke through various mechanisms including the secretion of neurotrophic factors, immunomodulation, the stimulation of endogenous neurogenesis, and neovascularization. To investigate the use of stem cell therapy for neurological diseases in preclinical studies, however, it is important to develop imaging technologies that are able to evaluate disease progression and to "chase" (i.e., track or monitor) transplanted stem cells in recipients. Imaging technology development is rapidly advancing, and more sensitive techniques, such as the invasive and non-invasive multimodal techniques, are under development. Here, we summarize the potential risk factors and biomarker treatment strategies, stem cell-based therapy and emerging multimodal imaging techniques in the context of stroke. This current review provides a conceptual framework for considering the therapeutic targets and directions for the treatment of brain dysfunctions, with a particular focus on ischemic stroke.

摘要

中风是一种严重的不良神经事件,是全球第三大致死和致残原因。大多数中风是由脑血流阻塞引起的,导致脑组织死亡从而出现神经功能缺损。重组组织型纤溶酶原激活剂(rt-PA)是目前唯一用于中风的即时治疗药物。使用rt-PA的目的是通过溶栓来减少血栓和/或栓塞;然而,rt-PA必须在症状发作后的非常短的治疗时间窗(3小时至6小时)内使用。缺血性中风所涉及的病理机制的组成部分可作为当前治疗中的潜在生物标志物。然而,目前尚无临床试验对其进行研究;因此,需要进一步开展研究生物标志物的研究。缺血性中风后,小胶质细胞可被激活并释放炎性细胞因子。在诸如中风等长期持续的损伤中,这些细胞因子会通过小胶质细胞的过度激活导致严重的神经毒性。因此,小胶质细胞激活的平衡调节可能是治疗所必需的。干细胞疗法是一种有前景的缺血性中风临床治疗策略。干细胞可通过多种机制促进缺血性中风后受损组织的功能恢复,这些机制包括分泌神经营养因子、免疫调节、刺激内源性神经发生和血管生成。然而,在临床前研究中,要研究干细胞疗法用于神经疾病的情况,开发能够评估疾病进展并“追踪”(即跟踪或监测)受体中移植干细胞的成像技术很重要。成像技术发展迅速,更敏感的技术,如侵入性和非侵入性多模态技术正在开发中。在此,我们总结了中风背景下的潜在危险因素和生物标志物治疗策略、基于干细胞的疗法以及新兴的多模态成像技术。本综述提供了一个概念框架,用于考虑脑功能障碍治疗的治疗靶点和方向,尤其关注缺血性中风。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8a8/8065883/d645b439f96b/pharmaceuticals-14-00321-g001.jpg

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