基于神经血管单元探讨中医药治疗缺血性脑损伤的研究思路
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摘要
缺血性脑损伤是由多种细胞相互作用引起的级联反应,以往主要针对特定神经元或血脑屏障等结构进行研究,而忽略了大脑各个功能区的整体联系性和不同结构之间的相互作用。近年来脑保护的目标已逐步由单一结构转变为对神经和血管整体的保护,并提出神经血管单元(NVU)这一概念。研究发现NVU内存在着多种双向细胞-细胞间和细胞-细胞外基质的相互作用,这种相互作用主要由神经元、胶质细胞、血管内皮细胞和细胞外基质共同构成。当脑组织缺血缺氧时,NVU整体结构功能破坏,引起胶质细胞活化/血管内皮细胞结构改变/血脑屏障通透性破坏等一系列动态的病理变化。故在治疗过程中,以NVU整体结构为靶点,协调其内部神经元-胶质细胞-血脑屏障-细胞外基质的动态变化,对减轻神经损伤与促进其修复具有重要意义。中医药具有整体调节和综合治疗优势,在保护NVU整体与各个组分的结构功能作用显著,已成为改善缺血性脑损伤及其机制研究领域的热点。因此,基于NVU的变化深入研究中医药保护缺血性脑损伤的作用机制,在诸多靶点中选择有效的药物干预,能够为中医药治疗缺血性脑损伤提供新的治疗思路。
Ischemic brain injury is a cascade reaction caused by multiple cellular interactions. Previous studies focused on specific neurons or blood-brain barrier structures, ignoring the global connectivity of various functional regions of the brain and the interaction between different structures. In recent years, the target of brain protection has gradually changed from a single structure to the protection of the whole nerve and blood vessel, and the concept of neurovascular unit(NVU) has been proposed. It is found that there are many bidirectional cell-cell and cell-extracellular matrix interactions in NVU, which are mainly composed of neurons, glial cells, vascular endothelial cells and extracellular matrix. During cerebral ischemia and hypoxia, the whole structure and function of NVU were destroyed, which caused a series of dynamic pathological changes, such as glial cell activation, vascular endothelial cell structure changed and blood-brain barrier permeability damaged. Therefore, in the course of treatment, it is important to take the whole structure of NVU as the target and coordinate the dynamic changes of the inner neuron, glial cell, blood-brain barrier and extracellular matrix in order to alleviate the nerve injury and promote its repair. Traditional Chinese medicine(TCM) has an advantage of holistic regulation and comprehensive therapy and plays a significant role in the protection of the structure and function of the whole and various components of NVU and becomes a hot spot in the research field of improving ischemic brain injury and its mechanism. Therefore, based on the in-depth study of NUV's mechanism of TCM's protection against ischemic brain injury, researchers can choose more effective interventions among many targets in the future, and thus providing new therapeutic ideas for TCM treatment of ischemic brain injury.
Ischemic brain injury is a cascade reaction caused by multiple cellular interactions. Previous studies focused on specific neurons or blood-brain barrier structures, ignoring the global connectivity of various functional regions of the brain and the interaction between different structures. In recent years, the target of brain protection has gradually changed from a single structure to the protection of the whole nerve and blood vessel, and the concept of neurovascular unit(NVU) has been proposed. It is found that there are many bidirectional cell-cell and cell-extracellular matrix interactions in NVU, which are mainly composed of neurons, glial cells, vascular endothelial cells and extracellular matrix. During cerebral ischemia and hypoxia, the whole structure and function of NVU were destroyed, which caused a series of dynamic pathological changes, such as glial cell activation, vascular endothelial cell structure changed and blood-brain barrier permeability damaged. Therefore, in the course of treatment, it is important to take the whole structure of NVU as the target and coordinate the dynamic changes of the inner neuron, glial cell, blood-brain barrier and extracellular matrix in order to alleviate the nerve injury and promote its repair. Traditional Chinese medicine(TCM) has an advantage of holistic regulation and comprehensive therapy and plays a significant role in the protection of the structure and function of the whole and various components of NVU and becomes a hot spot in the research field of improving ischemic brain injury and its mechanism. Therefore, based on the in-depth study of NUV's mechanism of TCM's protection against ischemic brain injury, researchers can choose more effective interventions among many targets in the future, and thus providing new therapeutic ideas for TCM treatment of ischemic brain injury.
引文
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[11] Olah M, Amor S, Brouwer N, et al. Identification of a microglia phenotype supportive of remyelination[J]. Glia, 2012, 60(2):306-321.
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[15] Alvarez JI, Katayama T, Prat A. Glial influence on the blood brain barrier[J]. Glia, 2013, 61(12):1939-1958.
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[17] Kang EJ, Major S, Jorks D, et al. Blood-brain barrier opening to large molecules does not imply blood-brain barrier opening to small ions[J]. Neurobiol Dis, 2013, 52:204-218.
[18] Weissa N, Millera F, Cazaubon S. The blood-brain barrier in brain homeostasis and neurological diseases[J]. Biochim Biophys Acta, 2009, 1788(4): 842-857.
[19] Janigro D. Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood-brain barrier[J]. Epilepsia, 2012, 53(1): 26-34.
[20] Benarroch EE. Blood-brain barrier: recent developments and clinical correlations[J]. Neurology, 2012, 78(16):1268-1276.
[21] Lim DA, Huang YC, Alvarez-Buylla A. The adult neural stem cell niche: lessons for future neural cell replacement strategies[J]. Neurosurg Clin N Am, 2007, 18(1): 81-92.
[22] Strbian D, Durukan A, Pitkonen M, et al. The blood brain barrier is continuously open for several weeks following transient focal cerebral ischemia[J]. Neuroscience, 2008, 153(1):175-181.
[23] 周虎传, 张玉波, 刘磊. 血脑屏障结构的细胞学与分子学机制的研究现状[J]. 2016, 19(11):98-99.
[24] Persidsky Y, Heilman D, Haorah J, et al. Rho-mediated regulation of tight junction during monocyte migration across blood-brain barrier in HIV-1 encephalitis ( HIVE)[J]. Blood, 2006, 107(12):4770-4880.
[25] Dejana E, Tournier-Lasserve E, Weinstein BM. The control of vascular integrity by endothelial cell junctions molecular basis and pathological implication[J]. Dev Cell, 2009,16(2):209-221.
[26] Saunders NR, Dziegielewska KM, Unsicker K, et al. Delayed astrocytic contact with cerebral blood vessels in FGF-2 deficient mice does not compromise permeability properties at the developing blood-brain barrier[J]. Dev Neurobiol, 2016, 76(11): 1201-1212.
[27] McRae M, LaFratta LM, Nguyen BM, et al. Characterization of cell-cell junction changes associated with the formation of a strong endothelial barrier[J]. Tissue Barriers, 2018, 6(1):e1405774.
[28] Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches[J]. Brain Res Rev, 2010, 64(2):328-363.
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