氨甲酰促红细胞生成素的神经保护作用及机制的研究进展

氨甲酰促红细胞生成素(Carbamylated erythropoietin,CEPO)是促红细胞生成素(Erythropoietin,EPO)的一种衍生物,与EPO一样具有神经保护作用,但是没有其造血功能。已有大量实验研究证实了CEPO的神经保护作用,并有最新研究阐述了EPO和CEPO具有不同的信号转导通路。本文主要介绍了CEPO的减轻神经细胞水肿、促进神经细胞分化、改善神经功能恢复等神经保护作用及CEPO可能通过激活CEPO受体、CD131、神经胶质细胞源性的神经营养因子(Glial cell line derived neurotrophic factor,GDNF)、蛋白激酶B(Protein kinase B,Akt)等机制发挥其神经保护作用。     

脑源性促红细胞生成素在短暂性前脑缺血沙土鼠海马的表达变化

目的 探讨短暂性前脑缺血鼠海马脑源性促红细胞生成素蛋白的表达变化,揭示脑缺血时中枢神经系统发生内源性脑保护的机制。方法 阻断沙土鼠双侧颈总动脉3．5min造成前脑缺血模型,再灌注1h,6h,12h,1d,3d,7d,应用免疫组织化学和免疫印迹法观察海马脑源性促红细胞生成素蛋白的表达变化。结果 脑缺血再灌注6h,可检测到脑源性促红细胞生成素的表达,再灌注12h,脑源性促红细胞生成素表达达到较高水平,以后随时间延长逐渐下调。结论 脑源性促红细胞生成素在脑缺血再灌注后的表达,可能是机体发生内源性脑保护的机制之一。     

促红细胞生成素在神经损伤中的作用

促红细胞生成素是控制红细胞生成的细胞因子,促红细胞生成素及受体在中枢和外周神经系统均有表达,发挥神经保护作用,有潜在的临床应用前景.本文对促红细胞生成素在外周神经损伤中的作用及机制作一综述,以求为外周神经损伤治疗提供新思路.     

促红细胞生成素在低氧预适应中的神经保护作用

促红细胞生成素(EPO)是体内一种重要的糖蛋白激素,主要由胎肝和成人的肾脏产生。EPO的表达除受到转录因子的调控之外,还受到表观遗传学的调控。研究发现,EPO及其受体(EPOR)在中枢神经系统中广泛表达,提示其对中枢系统具有神经保护作用。低氧预适应是机体抗缺氧或缺血的一种内源性保护机制,它可以促进EPO表达,减轻低氧/缺血引起的神经元损伤。EPO主要通过激活一系列信号转导通路及多种可能的机制发挥神经保护作用。     

维甲酸在脑缺血及卒中后抑郁中的作用

脑缺血及缺血后再灌注过程的病理生理机制复杂，发病后可能伴随卒中后抑郁等精神障碍，对人类生命和生活质量产生很大的威胁。目前的溶栓和取栓治疗具有极大限制性，寻求一种理想的神经保护药物对于治疗脑缺血有极其重要的临床意义。近年研究发现维甲酸不仅可通过调节炎症反应、保护血脑屏障、抗凋亡、促进神经再生等过程对脑缺血性疾病发挥保护作用，并且血清维甲酸水平在脑缺血及卒中后抑郁中可作为一项独立的指标发挥预测作用。该文将针对维甲酸在脑缺血及卒中后抑郁中的作用进行综述。     

营养因子调控脑缺血后内源性神经发生的研究进展

目前成年神经发生的调节机制及其在脑缺血后功能修复中的作用尚不清楚,研究表明神经发生受体内外多种信号分子的调控,许多内源性营养因子影响脑缺血后神经干细胞的增殖、迁移和分化.本文就多种营养因子对脑缺血后内源性神经发生的调控研究进展和存在的问题作一综述.     

PACAP对神经系统疾病保护作用的研究进展

垂体腺苷酸环化酶激活肽(pituitary adenylate cyclase-activating polypeptide,PACAP)存在于中枢神经系统内,作为神经递质、神经调质、神经营养因子及生长因子通过多种途径发挥神经保护作用.对脑缺血-再灌注损伤、创伤性脑损伤、精神分裂症、焦虑症、帕金森病、阿尔茨海默病等重大疾病具有重要的神经保护作用.本文就PACAP对神经系统疾病的保护作用及其机制的研究进行综述.     

神经营养因子与神经干细胞

生长因子在神经干细胞的增殖,分化和存活过程中有重要作用。神经营养因子是其中的一类,它包括神经生长因子（NGF）家族,胶质源性神经营养因子（GDNF）家族和其它神经营养因子。NGF家族包括NGF,BDNF,NT－3,NT－4／5和NT－6。这一家族可促进epidermic growth facter(EGF)反应 海马及前脑室管膜下区神经干细胞的存活和分化。GDNF家族包括GDNF,NTN,PSP和ART。GDNF家族促神经发育的作用主要在外周,它促进肠神经嵴前体细胞的存活和增殖,且对外周感觉神经的发育至关重要。其它生长因子如bFGF和EGF,它们能促进神经干细胞增殖和存活;CNTF和LIF等在神经干细胞的分化中也有重要作用。     

PI3K/AKT通路在红细胞生成素肾保护中的作用

红细胞生成素作为临床上最常用的纠正贫血的药物,近年随着研究的不断深入,其非造血的组织器官保护作用逐渐被认识。PI3K/AKT通路作为介导红细胞生成素生物学作用的通路之一,在红细胞生成素对各种急慢性肾脏疾病的保护过程中占据重要地位。本文就PI3K/AKT通路在红细胞生成素肾保护中的作用方面的研究进展作一综述。     

重组人促红细胞生成素纯化的研究进展

促红素能促进人前体红细胞的增殖和分化,从而使人体内红细胞数量增加。临床上主要用于贫血、组织断离以及癌症患者透析后的恢复。促红细胞生成素自1971年在羊的尿液中被提取出后,近30年以来人们不断对其进行研究。促红素蛋白纯化工艺从Myake的七步法完善到现在的三步纯化法。本文综述了促红细胞生成素蛋白纯化的发展历史以及促红素未来的发展方向。     

Neurotrophin-3, TNF-alpha and IL-6 relations in serum and cerebrospinal fluid of ischemic stroke patients

Pro-inflammatory cytokines and neurotrophins in the central nervous system (CNS) have been recognized as mediators of both neurodegenerative and neuroprotective mechanisms in a number of CNS pathologies. A rapid, sustained elevation of these molecules was recently reported after traumatic and ischemic brain injury. Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of cerebral ischemia. Stroke is the third largest cause of death next to heart disease and cancer in the world, and it is an important cause of death and disability in developed countries. Role of excitatory amino acids receptors activation, calcium overload, nitric oxide and oxidative stress in the pathogenesis of ischemic brain damage is well established. Stroke may modulate peripheral neurotrophic factors levels. In experimental animal models, neurotrophin-3 (NT-3) has been shown to be produced by glial cells as an adaptability response to hypoxia. In spite of substantial research and significant number of neuroprotective drugs that have been developed to limit ischemic brain damage and to improve the outcome for stroke patients, no specific therapy for stroke is available. The neurotrophins have been proposed as therapeutic agents for the treatment of neurodegenerative disorders and ischemic injury. In the present work, we investigated the possible correlation of NT-3 with tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the serum and cerebrospinal fluid (CSF) from patients with ischemic stroke (IS).     

Synthesis and c-Src inhibitory activity of imidazo[1,5-a]pyrazine derivatives as an agent for treatment of acute ischemic stroke

We synthesized and evaluated a series of C-5 substituted imidazo[1,5-a]pyrazine derivatives to identify potent c-Src inhibitors as potential therapeutic agents for acute ischemic stroke. Among these compounds, compound 14c.HCl demonstrated remarkable central nervous system (CNS) penetration and significant neuroprotective efficacy in vivo in rat models.     

The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection

BACKGROUND: The complement cascade plays a deleterious role in multiple models of ischemia/reperfusion (I/R) injury, including stroke. Investigation of the complement cascade may provide a critical approach to identifying neuroprotective strategies that can be effective at clinically relevant time points in cerebral ischemia. This review of the literature describes the deleterious effects of complement activation in systemic I/R models and previous attempts at therapeutic complement inhibition, with a focus on the potential role of complement inhibition in ischemic neuroprotection. Translation of these concepts into ischemic stroke models and exploration of related neuroprotective strategies are also reviewed. SUMMARY OF REVIEW: We performed a MEDLINE search to identify any studies published between 1966 and 2001 dealing with complement activation in the setting of I/R injury. We also searched for studies demonstrating up-regulation of any complement components within the central nervous system during inflammation and/or ischemia. CONCLUSIONS: The temporal and mechanistic overlap of the complement cascade with other biochemical events occurring in cerebral I/R injury is quite complex and is only beginning to be understood. However, there is compelling evidence that complement is quite active in the setting of acute stroke, suggesting that anticomplement strategies should be further investigated through genetic analysis, nonhuman primate models, and clinical investigations.     

Guanosine and its role in neuropathologies

Guanosine is a purine nucleoside thought to have neuroprotective properties. It is released in the brain under physiological conditions and even more during pathological events, reducing neuroinflammation, oxidative stress, and excitotoxicity, as well as exerting trophic effects in neuronal and glial cells. In agreement, guanosine was shown to be protective in several in vitro and/or in vivo experimental models of central nervous system (CNS) diseases including ischemic stroke, Alzheimer’s disease, Parkinson’s disease, spinal cord injury, nociception, and depression. The mechanisms underlying the neurobiological properties of guanosine seem to involve the activation of several intracellular signaling pathways and a close interaction with the adenosinergic system, with a consequent stimulation of neuroprotective and regenerative processes in the CNS. Within this context, the present review will provide an overview of the current literature on the effects of guanosine in the CNS. The elucidation of the complex signaling events underlying the biochemical and cellular effects of this nucleoside may further establish guanosine as a potential therapeutic target for the treatment of several neuropathologies.     

Systems Neuroprotective Mechanisms in Ischemic Stroke

Ischemic stroke, although causing brain infarction and neurological deficits, can activate innate neuroprotective mechanisms, including regional mechanisms within the ischemic brain and distant mechanisms from non-ischemic organs such as the liver, spleen, and pancreas, supporting neuronal survival, confining brain infarction, and alleviating neurological deficits. Both regional and distant mechanisms are defined as systems neuroprotective mechanisms. The regional neuroprotective mechanisms involve release and activation of neuroprotective factors such as adenosine and bradykinin, inflammatory responses, expression of growth factors such as nerve growth factors and neurotrophins, and activation and differentiation of resident neural stem cells to neurons and glial cells. The distant neuroprotective mechanisms are implemented by expression and release of endocrine neuroprotective factors such as fibroblast growth factor 21, resistin like molecule γ, and trefoil factor 3 from the liver; brain-derived neurotrophic factor and nerve growth factor from the spleen; and neurotrophin 3 and vascular endothelial growth factor C from the pancreas. Furthermore, ischemic stroke induces mobilization of bone marrow hematopoietic stem cells and endothelial progenitor cells into the circulatory system and brain, contributing to neuroprotection. The regional and distant mechanisms may act in coordination and synergy to protect the ischemic brain from injury and death. This paper addresses these mechanisms and associated signaling networks.     

Kalirin,一种新的神经保护因子的研究进展

Kalirin是一种胞质内蛋白,属于Dbl(Diffuse B lymphoma)癌基因家族的一员,由于其与PAM(一种对神经肽生物合成所必需的酶)相互作用而首次被发现.主要在成年大鼠的中枢神经系统中永久性高表达,在胚胎中的表达比在成年鼠更加普遍,既在神经组织中表达也在非神经组织中表达.Kalirin能够激发神经元突起的生长、提高树突棘的数量在协调内分泌、神经轴突的生长、突触的发育、大脑的成熟等过程中发挥极其重要的作用.Kalirin作为神经保护因子为中枢神经系统的退行性及急性损伤相关疾病提供新的治疗线索,有着非常广泛的应用前景.就Kalirin的发现、分子结构、亚基、分布、在神经系统保护等方面的应用前景进行综述.     

Hematopoietic cytokines--on the verge of conquering neurology

Two hematopoietic cytokines are currently gaining increasing attention within neurological research. Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have long been known for their ability to induce the proliferation of certain populations of hematopoietic lineage cells. However, it has recently been found that EPO, G-CSF, and their respective receptors are also expressed in the human central nervous system (CNS) and may be an important part of the brain's endogenous system of protection. Both hematopoietic cytokines have been shown to have neuroprotective potential in a variety of animal disease models both in vitro and in vivo, through the inhibition of apoptosis, induction of angiogenesis, exertion of anti-inflammatory and neurotrophic effects, as well as by the enhancement of neurogenesis. EPO and G-CSF have been extensively studied in the context of hematological disorders and have recently been successfully applied in the first clinical trials in stroke patients. Intravenous high-dose EPO therapy was associated with an improvement in the clinical outcome and preclinical studies with intravenous high-dose G-CSF therapy have clearly shown that it has considerable neuroprotective potential in the acute, as well as in the chronic phase of stroke. In this review, the current knowledge of the neuroprotective mechanisms of EPO and G-CSF is summarized with regard to in vitro and in vivo data. Focus is placed on the role of EPO in neurological disease models with an emphasis on its influence on functional outcome. New experimental results are assessed in detail and correlated with the findings of recent clinical studies.     

Blockade of glutamate excitotoxicity and its clinical applications

Glutamate has long been known to play a vital role in the normal functioning of neurons, serving as the main excitatory neurotransmitter in the central nervous system. The normal function of glutamate, as a means of communication from one neuron to the next, breaks down in certain disease states. Under particular scrutiny has been the etiology of neuronal damage caused by ischemic disease, seen most commonly in cerebrovascular embolic disease, commonly known as a stroke. It has been shown that damage associated with ischemic disease in the brain is not a direct result of hypoxia or deprivation of metabolic intermediates. In fact, the crucial role is played by an excessive efflux of glutamate by ischemic neurons, which then in turn activates pathways in post-synaptic neurons leading to acute cell swelling and later, cell death. An extremely hopeful development in the field of glutamate excitotoxicity has been the application of therapeutic methods aimed at attenuating the damaging action of glutamate, in an effort to decrease morbidity associated with such common diseases as stroke and other neurodegenerative disorders.Special issue dedicated to Dr. Claude Baxter.     

Therapeutic Strategy for Ischemic Stroke

Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes. Special issue article in honor of Dr. Akitane Mori.