促红细胞生成素在中枢神经系统缺氧/缺血时的保护作用

促红细胞生成素(Erythropoietin,Epo)因在红细胞生成时发挥重要作用而被认识,但是Epo也产生和分布于中枢神经系统(central nervous system,CNS).缺氧时,Epo通过对神经干细胞的调节,对抗细胞凋亡,发挥神经营养作用,因而对CNS具有保护功能.目前,对Epo所介导的细胞内信息传递已有所认识,很可能为CNS缺氧/缺血性疾病的治疗开辟新途径.     

促红细胞生成素神经保护作用的研究进展

<正>促红细胞生成素(erythropoietin,EPO)是一种刺激人体造血器官、促进红细胞生成的糖蛋白类激素。近年来,EPO作为中枢神经系统(Central nervous system,CNS)的神经营养因子,具有促进CNS的生长发育及神经保护作用,其在CNS中的影响受到关注。我们应用万方、pubmed等数据库,检索了近年来国内外报道EPO对CNS保护作用的相关文章,探讨并总结该作用的可能机制及EPO对CNS疾病的治疗前景,就以上内容综述如下。1 EPO神经保护作用的可能机制     

促红细胞生成素的神经保护功能

近来研究发现促红细胞生成素(Epo)及其功能受体(Epo-R)在中枢神经系统中也有表达,且具有神经保护功能,本文就Epo在神经系统中的表达调节及其可能的神经保护机制,如抗凋亡、抑制炎性反应、抗谷氨酸毒性、抗NO及氧化反应、对神经递质的影响、维护血管完整性及刺激新生血管形成、诱导神经营养因子的表达、调节神经发生和神经营养作用及其在缺血预处理中的作用等方面略做一综述.     

兴奋性氨基酸与脑缺血/缺氧预适应

脑缺氧/缺血、药物等多种因素产生的预适应现象都具有显著的组织器官保护作用.以往多数研究涉及兴奋性氨基酸在脑缺血缺氧时对神经细胞的损害作用，目前越来越多研究表明脑缺血/缺氧预适应时，神经元释放EAA通过NMDA受体使钙离子内流增加，激活下游的蛋白激酶C（PKC），MAPK等信号通路，发挥着神经细胞保护作用.此外，在脑缺血缺氧预适应中EAA通过非NMDA受体也发挥神经保护作用。     

星形胶质细胞在中枢神经系统中的保护作用

正星形胶质细胞是一把双刃剑,对中枢神经系统(central nervous system, CNS)既有神经毒性作用,同时又有神经保护作用。本文从结构、代谢和抗损伤方面就星形胶质细胞在CNS疾病中的作用及机制做一综述,以对星形胶质细胞的功能有一个更全面的认识。一、结构、代谢及相关功能1.调节脑血流量大脑重量占体质量的2%,而血流却占心排量的12%～15%,可见脑血流量对正常脑功能的发挥有至关重要的作用,而星形胶质细胞是CNS调节脑血流量的主要细胞,故研究星形胶质细胞对脑血流量的调节具有重要意义。     

中枢神经病毒感染的病理及生物化学机制

近年来在中枢神经系统(CNS)病毒感染发病机制的认识上取得较大进展。本综述了病毒的传播、细胞群的选择性易损性、病毒的组织亲嗜性和神经毒力特性在CNS感染发病机制中的作用。病毒产生有意义的CNS感染的潜力差异极大，CNS感染的发病取决于病毒对神经的亲嗜性，分子病毒学的研究强调了影响和决定这种亲嗜性的机制，包括病毒和宿主两方面的遗传因素。     

重症肌无力中枢损害脑内神经胶质细胞的变化

目的　为了探讨神经胶质细胞凋亡在重症肌无力 ( MG)中枢神经系统 ( CNS)受损机制中的作用。方法　将 MG患者血中 Ig G ( ACh RAb)注入大鼠侧脑室 ,建立 MG大鼠中枢损害模型 ,并应用透射电镜来观察该模型大鼠中枢神经胶质细胞凋亡情况。结果　侧脑室注射 ACh RAb后 ,在 MG中枢损害模型大鼠海马及大脑皮层可见神经胶质细胞凋亡。结论　在 MG中枢损害机制中 ,神经胶质细胞凋亡可能发挥重要作用。 ACh RAb与CNS内神经 -ACh R结合 ,导致包括神经胶质细胞凋亡在内的 CNS损害 ,引起 CNS功能障碍。     

促红细胞生成素对外伤性脑损伤的保护作用

促红细胞生成素(Erythropoietin,EPO)除了促进红细胞成长以外,还具有抗炎、抗细胞凋亡、神经营养和神经保护作用;中枢神经系统(CNS)中的星形胶质细胞可以通过旁分泌方式分泌EPO,然后通过EPO-R发挥作用;EPO在外伤性颅脑损伤中具有抗凋亡、减轻脑水肿、促进神经细胞再生、减少兴奋性氨基酸神经毒性及抗氧化的作用;新型外源性EPO能透过血脑屏障,其临床应用前景看好.     

短暂性前脑缺血沙土鼠脑内促红细胞生成素的表达变化

促红细胞生成素 (erythropoietin ,Epo)具有神经保护和促进血管形成双重作用[1 ] ,在局灶性持续性脑缺血小鼠脑内存在Epo的表达[2 ] 。本研究观察短暂性前脑缺血沙土鼠脑内Epo的表达情况 ,探讨脑缺血时神经系统发生的内源性保护的机制。1　资料1 1　动物模型 :雄性沙土鼠 4 2只 ,6 0～ 80g( 9～ 12周龄 )由浙江省实验动物中心提供。随机分为假手术对照组和短暂性前脑缺血再灌注组。用无损伤血管夹夹闭双侧颈总动脉 3 5min,松夹后恢复血流 1h、6h、12h、1d、3d、7d。手术过程中及术后 ,用加热垫和灯泡保持肛温在 37～ 37 5℃。假手术组除不…     

促红细胞生成素(EPO)的神经保护作用

促红细胞生成素(erythropoietin，EPO)是调节红细胞生成的糖蛋白，主要产生于胎儿的肝脏和成人的肾脏，EPO和它的受体主要存在于骨髓的造血干细胞并刺激它向红细胞分化。但最近的研究表明，功能性的EPO受体在许多的组织和器官中都有表达，包括神经系统的神经细胞、胶质细胞和血管内皮细胞。EPO和它的受体在脑缺血、缺氧和贫血时表达上调，暗示它有内源性神经保护作用。本文回顾了EPO对神经保护作用的相关文献，对其神经保护作用的机制、信号传导途径的调节以及EPO可能治疗的中枢神经系统疾病作一综述。     

Neuroprotective effects and mechanisms of ischemic/hypoxic preconditioning on neurological diseases

As the organ with the highest demand for oxygen, the brain has a poor tolerance to ischemia and hypoxia. Despite severe ischemia/hypoxia induces the occurrence and development of various central nervous system (CNS) diseases, sublethal insult may induce strong protection against subsequent fatal injuries by improving tolerance. Searching for potential measures to improve brain ischemic/hypoxic is of great significance for treatment of ischemia/hypoxia related CNS diseases. Ischemic/hypoxic preconditioning (I/HPC) refers to the approach to give the body a short period of mild ischemic/hypoxic stimulus which can significantly improve the body's tolerance to subsequent more severe ischemia/hypoxia event. It has been extensively studied and been considered as an effective therapeutic strategy in CNS diseases. Its protective mechanisms involved multiple processes, such as activation of hypoxia signaling pathways, anti-inflammation, antioxidant stress, and autophagy induction, etc. As a strategy to induce endogenous neuroprotection, I/HPC has attracted extensive attention and become one of the research frontiers and hotspots in the field of neurotherapy. In this review, we discuss the basic and clinical research progress of I/HPC on CNS diseases, and summarize its mechanisms. Furthermore, we highlight the limitations and challenges of their translation from basic research to clinical application.     

Regulation of Hypoxia-Induced Inflammatory Responses and M1-M2 Phenotype Switch of Primary Rat Microglia by Sex Steroids

Microglia cells are the primary mediators of the CNS immune defense system and crucial for the outcome of shaping inflammatory responses. They are highly dynamic, moving constantly, and become activated by neuronal signaling under pathological conditions. They fulfill a dual role by not only regulating local neuroinflammation but also conferring neuronal protection. Gonadal steroids are known to exert anti-inflammatory effects in the CNS. Recently, we have shown that the microglial-like cell line BV-2 is hypoxia-sensitive and regulated by gonadal steroids. The present study used primary rat cerebral cortex-derived microglia to analyze whether this cell type directly perceive and respond to acute hypoxia. Second, we investigated whether 17β-estradiol (E2) and progesterone (P) interfere with hypoxia-induced changes. Short-term hypoxia increased the expression of a subset of pro-inflammatory (TNFa, IL1b) and oxidative stress-related (Hif1a) genes. The induction of TNFa and IL1b was counteracted by P. Hypoxia shifted the primary microglia to the pro-inflammatory M1 phenotype. The administration of E2 and P favored the neuroprotective M2 phenotype. Our findings extend previous data obtained with BV-2 cells and show that the primary microglia directly perceive hypoxia which increase their inflammatory activity. Both steroid hormones directly and indirectly interact with the microglia cells by reducing the inflammatory scenario and stimulating neuroprotection.     

Neurotransmitter glutamate: its clinical importance

Excitatory amino acid glutamate has several important functions in the mammalian central nervous system (CNS). This review focuses on the transmitter role of glutamate and discusses anatomical and pharmacological data of clinical neurological relevance. Experimental and clinical conditions which have been associated with altered content, uptake, membrane binding or release of glutamate in the CNS are discussed. Such conditions include, epilepsy, disorders of the basal ganglia, cerebral ischemia, hypoxia, hypoglycemia, metabolic encephalopathies, olivopontocerebellar atrophy and cerebellar ataxias, amino acidopathies, mental and other neurological disorders. With the exception of a few fibre systems, it is very difficult to differentiate between glutamate and aspartate as CNS transmitters. The term glutamate is, thus, used in the sense glutamate and/or aspartate unless specifically stated.     

Increased expression of fibronectin and the alpha 5 beta 1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia

The extracellular matrix (ECM) is an important regulator of angiogenesis and vascular remodeling. We showed previously that angiogenic capillaries in the developing CNS express high levels of fibronectin and its receptor alpha5beta1 integrin, and that this expression is developmentally downregulated. As cerebral hypoxia leads to an angiogenic response, we sought to determine whether angiogenic vessels in the adult CNS re-express fibronectin and the alpha5beta1 integrin. Ten-week old mice were subject to hypobaric hypoxia for 0, 4, 7 and 14 days, and fibronectin/integrin expression examined. Fibronectin and the alpha5 integrin subunit were strongly upregulated on capillaries in the hypoxic CNS, with the effect maximal at the earliest time point examined (4 days). Immunofluorescent studies demonstrated that the alpha5 integrin was expressed by angiogenic endothelial cells. In light of the defined angiogenic role for fibronectin in other systems, this work suggests that induction of fibronectin-alpha5beta1 integrin expression may be an important molecular switch driving angiogenesis in the hypoxic CNS.     

Microglia modulate respiratory rhythm generation and autoresuscitation

Inflammation has been linked to the induction of apneas and Sudden Infant Death Syndrome, whereas proinflammatory mediators inhibit breathing when applied peripherally or directly into the CNS. Considering that peripheral inflammation can activate microglia in the CNS and that this cell type can directly release all proinflammatory mediators that modulate breathing, it is likely that microglia can modulate breathing generation. It might do so also in hypoxia, since microglia are sensitive to hypoxia, and peripheral proinflammatory conditions affect gasping generation and autoresuscitation. Here, we tested whether microglial activation or inhibition affected respiratory rhythm generation. By measuring breathing as well as the activity of the respiratory rhythm generator (the preBötzinger complex), we found that several microglial activators or inhibitors, applied intracisternally in vivo or in the recording bath in vitro, affect the generation of the respiratory rhythms both in normoxia and hypoxia. Furthermore, microglial activation with lipopolysaccharide affected the ability of the animals to autoresuscitate after hypoxic conditions, an effect that is blocked when lipopolysaccharide is co‐applied with the microglial inhibitor minocycline. Moreover, we found that the modulation of respiratory rhythm generation induced in vitro by microglial inhibitors was reproduced by microglial depletion. In conclusion, our data show that microglia can modulate respiratory rhythm generation and autoresuscitation. GLIA 2016;64:603–619     

Perinatal hypoxia-/ischemia-induced endothelin-1 mRNA in astrocyte-like and endothelial cells.

Under pathological conditions in the adult CNS, such as ischemia, subarachnoid hemorrhage and Alzheimer's disease, endothelin (ET)-1- and -3-like immunoreactivities are elevated in astrocytes of the injured adult brain. However, it is not clear whether this is due to increased synthesis or increased binding of ET-1. Further, it is not known whether ET-1 expression is altered in the perinatal brain after cerebral hypoxia/ischemia (H/I). Here, we determined the sites of ET-1 expression in perinatal mouse brain after H/I injury by in situ hybridization using a probe specific for the ET-1 gene. Astrocyte-like cells, which do not normally express ET-1 mRNA, showed high levels of ET-1 mRNA expression. Endothelial cells of the capillaries and small vessels also showed an increased level of ET-1 mRNA. Our data suggest that ET-1 mRNA levels in the astrocyte-like cells and vascular endothelial cells are dynamically regulated by ischemia and may participate in perinatal ischemia-related neural damage.     

Antenatal hypoxia: Involvement in the development of CNS pathologies during ontogeny

We summarize the data describing the effects of antenatal hypoxia on the development of the fetal CNS. Hypoxia is one of the most widespread and clinically important stress factors, which may affect embryonic development and result in embryotoxic consequences and various developmental pathologies. Acute hypoxia may appear at different stages of pregnancy as an unspecific side effect of toxicosis, cardiovascular and respiratory diseases, smoking, or alcohol consumption, among other causes. Antenatal hypoxia plays a leading role in the delay of the biological development of the CNS and higher functions of the brain. Original Russian Text ? A.V. Graf, E.N. Goncharenko, N.A. Sokolova, I.P. Ashmarin, 2008, published in Neirokhimiya, 2008, Vol. 25, Nos. 1–2, pp. 11–16.     

De novo erythropoietin receptor (EPO-R) expression in human neoplastic glial cells decreases with grade of malignancy but is favourably associated with patient survival

The erythropoietin receptor (EPO-R) is mainly known as a regulator of erythropoiesis. However, recent studies revealed that the EPO-R is not exclusively expressed in haematopoietic tissues but also in various cancer cell types and normal tissue such as the central nervous system (CNS). EPO-R is up-regulated under hypoxia and is able to counteract the deleterious effects of hypoxia on tumour growth, metastasis and treatment resistance. Therefore, the EPO-EPO-R signalling pathway is considered as a possible target for tumour treatment. Here, we investigated brain tumour samples obtained from patients between 1993 and 2003 to study EPO-R expression in vivo. Tissue samples included 194 gliomas of different WHO grades, additionally 25 infiltration zone samples and 31 relapses of WHO grade IV glioblastomas as well as 23 normal CNS tissue specimens to address the in vivo situation. Immunohistochemistry of the tissue microarray samples revealed significantly higher levels of EPO-R expression in neoplastic glial cells compared with glial cells derived from normal brain. EPO-R expression showed a highly significant decrease from low- to high-grade gliomas. Age-stratified Kaplan-Meier analysis revealed longer survival for patients exhibiting high EPO-R status in high-grade gliomas. Our results show a grade-dependent EPO-R down-regulation and might contribute to the understanding of high-grade glioma resistance to radio- and chemotherapy as both were shown to be improved by a well functioning EPO-EPO-R pathway in previous studies. Further studies are needed to investigate to what extent the decreased mortality in age-stratified patient groups with high EPO-R levels reflects a direct beneficial role of EPO-R expression.     

In the hypoxic central nervous system,endothelial cell proliferation is followed by astrocyte activation,proliferation, and increased expression of the α6β4 integrin and dystroglycan

Cerebral hypoxia induces a profound angiogenic response in the central nervous system (CNS). Using a mouse model of chronic cerebral hypoxia, we previously demonstrated that angiogenic vessels in the hypoxic CNS show marked upregulation of the extracellular matrix (ECM) protein fibronectin, along with increased expression of its major receptor, α5β1 integrin on brain endothelial cells (BEC). As cerebral hypoxia also leads to glial activation, the aim of the current study was to define the temporal relationship between BEC responses and glial cell activation in this model of cerebral hypoxia. This revealed that BEC fibronectin/α5β1 integrin expression and proliferation both reached maximal level after 4‐day hypoxia. Interestingly, up to 4‐day hypoxia, all dividing cells were BEC, but at later time‐points proliferating astrocytes were also observed. GFAP staining revealed that hypoxia induced marked astrocyte activation that reached maximal level between 7‐ and 14‐day hypoxia. As newly formed cerebral capillaries require ensheathment by astrocyte end‐feet to acquire mature brain endothelium characteristics, we next examined how expression of astrocyte end‐feet adhesion molecules is regulated by hypoxia. This showed that the astrocyte adhesion receptors α6β4 integrin and dystroglycan were both markedly upregulated, with a time‐course that closely resembled astrocyte activation. Taken together, this evidence shows that cerebral hypoxia promotes first an endothelial response, in which fibronectin promotes BEC proliferation. This is then followed by an astrocyte response, involving astrocyte activation, proliferation, and reorganization of astrocyte end‐feet, which correlates with increased expression of astrocyte end‐feet adhesion molecules. © 2010 Wiley‐Liss, Inc.     

Risk Factors of Infantile Spasms Compared with Other Seizures in Children Under 2 Years of Age

Summary: To analyze the magnitude of the risk factors for infantile spasms, we evaluated the records of 80 children with infantile spasms, 474 children with other types of epilepsy, 2,196 children with febrile seizures, and 262 children with CNS infections. There was a family history of seizures in 13.8% of children with infantile spasms, 28.5% of children with other forms of epilepsy, 25.5% of children with febrile seizures, and 5.3% of children with CNS infections. Children with a family history of seizures were 2.82 times more likely to have infantile spasms, 7.05 times more likely to have other epilepsy, and 6.08 times more likely to have febrile seizures than controls (children with CNS infections). However, a family history of seizures increased the risk for infantile spasms only in the cryptogenic group. Children with infantile spasms were significantly more likely to have cerebral palsy, microcephaly, hydrocephaly, CNS malformations, neonatal hypoxia, or neonatal seizures than children with other types of epilepsy, febrile seizures, or CNS infections. There was a modest genetic predisposition to seizures in children with infantile spasms. However, our data suggest a much stronger association with underlying neurologic abnormalities, mainly neonatal seizures, neonatal hypoxia, and CNS malformations.