缺氧诱导因子1α与脑缺血缺氧性损伤

缺氧诱导因子1α(HIF-1α)是近年来研究较多的一种转录调节因子,其在常氧状态下降解,低氧状态下稳定,并从细胞质向细胞核转移,参与对低氧的多种生理应答,通过泛素蛋白酶体系统降解,在缺氧神经细胞培养及脑缺血缺氧损伤模型中表达增加,不同药物干预及高压氧预处理对其表达变化影响不同,产生神经保护或者损伤作用,通过研究其表达特点,为临床缺血缺氧性脑损伤的治疗提供新的思路。     

内源性神经保护因子花生四烯酰多巴胺的研究进展

正哺乳动物体内存在内源性大麻素系统,该系统包括内源性大麻素、大麻素受体以及合成、运输和降解它们的酶。花生四烯酰多巴胺(N-arachidonoy ldopamine,NADA)是一种重要的内源性大麻素,在抗氧化、抗炎、免疫调节、抗兴奋毒性和调节突触可塑性等方面发挥着重要的神经保护作用,可作为神经退行性疾病治疗的新靶点。本研究就目前有关NADA、NADA受体及其病理生理功能进行综述,以期为中枢神经系统疾病的治疗提供新的思路。1 花生四烯酰     

脑红蛋白在缺血缺氧性脑损伤中保护机制的研究进展

脑红蛋白(neuroglobin,Ngb)是继血红蛋白、肌红蛋白之后发现的第3类携氧球蛋白。脑组织在缺血、缺氧状态下会诱导脑红蛋白高度表达,以保护神经元免受缺血性损害,但具体的神经保护功能及其分子作用机制尚不明了。本文就脑红蛋白的分布、结构特征及其在缺血缺氧性脑损伤(hypoxic-ischemic brain damage,HIBD)中可能的作用和保护机制作一简要综述。     

内源性大麻素系统和突触可塑性研究进展

突触可塑性是学习和记忆的神经基础,随着近些年对内源性大麻素系统研究的深入,内源性大麻素作为逆向信号分子在突触信号传递中发挥调节作用引起了重视。内源性大麻素系统介导的突触可塑性分为短期可塑性和长期可塑性,介导的短期可塑性又可分为:去极化介导的、受体介导的、Ca2+协助受体介导的、突触激发介导的四种内源性大麻素释放方式。内源性大麻素系统还参与神经胶质细胞和神经细胞粘附分子对突触可塑性的调节。现就内源性大麻素系统在调节突触可塑性生理机制的研究进展做一综述。     

纳洛酮治疗55例新生儿缺氧缺血性脑病的疗效观察

新生儿缺血缺氧性脑病（ＨＬＥ）是围产期新生儿缺血缺氧引起的脑部改变。脑组织的主要病理改变有水肿、软化、坏死和出血。围产期足月儿脑损伤最常见。据国外报道，大多数有脑瘫的儿童为足月儿，尽管足月儿脑瘫发病率为３．３８‰，较早产儿９０‰低，但足月儿占新生儿的９２％。若不及时、恰当治疗，易导致新生儿死亡、脑功能缺陷、智力障碍及癫痫病。１临床资料１．１一般资料 我院自１９９７～１９９９年收住ＨＬＥ５５例，均符合韩玉昆诊断标准［１］，随机分两组，治疗组２８例，男１４例，女１４例，轻度９例，中度１４例，重度５例…     

少突胶质细胞在早产儿缺血缺氧性脑损伤关键作用的研究进展

脑室周围白质软化(PVL)是早产儿缺血缺氧性脑损伤的最主要神经病理类型,少突胶质细胞(OLs)是PVL病变的关键靶细胞,本文阐明了早产儿缺血缺氧性脑损伤中少突胶质细胞损伤的机制,即通过氧自由基和兴奋性氨基酸直接或间接地造成少突胶质细胞损伤,最终导致脑室周围白质软化。随着对早产儿少突胶质细胞损伤的进一步研究,其损伤机制将得到更深入、更全面的阐明,这对临床治疗早产儿缺血缺氧性脑损伤具有指导意义。     

低温治疗急性缺血性卒中的研究进展

脑血管病作为神经系统的常见病及多发病,是目前导致人类死亡的三大主要疾病之一,也是第一大致残性疾病.缺血性卒中是脑血管病最常见的类型,约占脑血管病的70％.在现有的诸多治疗手段中,低温是有效的神经保护措施.自20世纪50年代低温的神经保护作用被发现以来,其已被提出用于外伤性脑损伤、卒中、心脏停搏性脑病、新生儿缺血缺氧性脑病、肝性脑病、脊髓损伤及动脉瘤手术等多个领域.本文根据近年来文献报道,就低温在急性缺血性卒中治疗中的研究进展进行综述,以期为开展低温的临床应用提供依据.     

低温在新生儿窒息复苏中的作用

窒息是新生儿最常见的症状和主要死亡原因。窒息时因脑的供氧量减少和脑血流下降 ,使脑组织能量代谢异常而发生一系列的病理生理改变 ,从而导致缺血缺氧性脑损伤。低温可以降低脑的能量利用率和脑的氧消耗量 ,增强细跑对缺血缺氧的耐受性 ,有良好的脑保护作用。本文就低温治疗新生儿窒息后脑损伤的历史、机制和其副作用作简要综述。     

丹参脑活素联合治疗新生儿缺血缺氧性脑病30例

正确处理新生儿缺血缺氧性脑病对降低围产期死亡率,预防和减少远期后遗症有重要意义。我科对30例新生儿缺血氧性脑病在常规治疗基础上加用丹参和脑活素疗效满意,报道如下。1资料与方法1．1病例选择我科于1993年1月～1997年1月收治新生儿缺血缺氧性脑病58例。全部患儿均有明显的围产期缺氧窒息史,生后12h内出现神经系统症状。均经CT证实,轻度：散在局灶低密度影分布2个脑叶内;中度：低密度影超过2个脑叶,白质灰质对比模糊;重度：弥漫性低密度影,灰白质界限消失,但基底节小脑尚有正常密度。所有患儿均符合1989年制定的HIE诊断及分…     

神经节苷脂GM1对缺血缺氧后脑中HSP70表达的影响

目的 研究神经节苷脂GM1对新生鼠缺血缺氧性脑损伤的保护作用及HSP70表达的影响。方法 建立新生鼠缺氧缺血性脑病动物模型,应用组织化学和免疫组织化学法观察缺血缺氧后3h、6h、1d、3d、7d、14d脑组织的病理变化及HSP70的表达,以及GM1给药后的变化。结果 单纯缺血缺氧组,在缺血缺氧后3h缺血侧皮层、海马CA3区、纹状体开始有少量HSP70表达,24h达高峰,14d未见HS70表达;GM1给药组,脑组织损伤明显减轻,6h才开始有少量HSP70表达,7d未见有表达。结论 GM1对新生鼠缺血缺氧性脑损伤具有明显的保护作用;HSP70的诱导表达是缺血缺氧性脑损伤敏感而可靠的指标,GM1可抑制这种表达。     

Differential effects of the antidepressants tranylcypromine and fluoxetine on limbic cannabinoid receptor binding and endocannabinoid contents

The goal of this study was to determine whether the endocannabinoid system is altered by chronic antidepressant treatment. The effects of 3-week administration of the monoamine oxidase inhibitor, tranylcypromine (10 mg/kg) and the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg) on cannabinoid CB₁ receptor densities and endocannabinoid contents were determined in limbic brain regions of the rat. Tranylcypromine significantly reduced tissue content of the endocannabinoid N-arachidonylethanolamine (anandamide) in the prefrontal cortex, hippocampus and hypothalamus and increased 2-arachidonoylglycerol content in the prefrontal cortex. Tranylcypromine treatment significantly increased CB₁ receptor binding density in the prefrontal cortex and hippocampus, but not in the hypothalamus. Treatment with fluoxetine increased CB₁ receptor density in the prefrontal cortex, but had no effect on endocannabinoid contents in any brain region examined. These data suggest that monoaminergic neurotransmission can regulate the endocannabinoid system and further indicates a role of the endocannabinoid system in affective illness and its treatment. An erratum to this article can be found at     

The endocannabinoid system and nondrug rewarding behaviours

Rewarding behaviours such as sexual activity, eating, nursing, parenting, social interactions, and play activity are conserved strongly in evolution, and they are essential for development and survival. All of these behaviours are enjoyable and represent pleasant experiences with a high reward value. Remarkably, rewarding behaviours activate the same brain circuits that mediate the positive reinforcing effects of drugs of abuse and of other forms of addiction, such as gambling and food addiction. Given the involvement of the endocannabinoid system in a variety of physiological functions of the nervous system, it is not surprising that it takes part in the complex machinery that regulates gratification and perception of pleasure. In this review, we focus first on the role of the endocannabinoid system in the modulation of neural activity and synaptic functions in brain regions that are involved in natural and nonnatural rewards (namely, the ventral tegmental area, striatum, amygdala, and prefrontal cortex). Then, we examine the role of the endocannabinoid system in modulating behaviours that directly or indirectly activate these brain reward pathways. More specifically, current knowledge of the effects of the pharmacological manipulation of the endocannabinoid system on natural (eating, sexual behaviour, parenting, and social play) and pathological (gambling) rewarding behaviours is summarised and discussed.     

The endocannabinoid system and neurogenesis in health and disease.

The endocannabinoid system exerts an important neuromodulatory function in different brain areas and is also known to be involved in the regulation of neural cell fate. Thus, CB(1) cannabinoid receptors are neuroprotective in different models of brain injury, and their expression is altered in various neurodegenerative diseases. Recent findings have demonstrated the presence of a functional endocannabinoid system in neural progenitor cells that participates in the regulation of cell proliferation and differentiation. In this Research Update, the authors address the experimental evidence regarding the regulatory role of cannabinoids in neurogenesis and analyze them in the context of those pathological disorders in which cannabinoid function and altered neuronal or glial generation is most relevant, for example, stroke and multiple sclerosis.     

The endocannabinoid system and energy metabolism

Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors [cannabinoid receptor type 1 (CB1) and CB2] participate in the physiological modulation of many central and peripheral functions. The ability of the endocannabinoid system to control appetite, food intake and energy balance has recently received considerable attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptors and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control several metabolic functions by acting on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, and therefore drugs interfering with this overactivation by blocking CB1 receptors are considered as potentially valuable candidates for the treatment of obesity and related cardiometabolic risk factors.     

The endocannabinoid system: A new entry in remote cell death mechanisms

Functional impairment after development of focal CNS lesions depends highly on damage that occurs in regions that are remote but functionally connected to the primary lesion site. These remote effects include cell death and structural changes, and they are important predictors of outcome in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the neuropathological mechanisms that exist in regions that are remote from focal primary lesions is therefore essential for the development of neuroprotective strategies.Endocannabinoids constitute a novel class of lipids that regulate mammalian cell apoptosis and the pathogenesis of neuroinflammatory and neurodegenerative diseases. In addition to well-described pharmacological actions in the brain, such as analgesia, hypokinesia, and hypothermia, endocannabinoids have been recently reported to control neuronal cell fate in various neuropathological conditions. Following brain injury, endocannabinoids are released, causing both protective and degenerative effects. Several hypotheses have been proposed to explain their role, but the mechanisms by which they act are largely unknown. New evidence indicates that the endocannabinoid system is a key participant in the determination of cell fate in remote cell death and its associated mechanisms. This review addresses recent findings on endocannabinoid function, focusing particularly on the relationships between the nitrergic, purinergic, and endocannabinoid systems.     

Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain

Recent evidence points to the gut microbiota as a regulator of brain and behavior, although it remains to be determined if gut bacteria play a role in chronic pain. The endocannabinoid system is implicated in inflammation and chronic pain processing at both the gut and central nervous system (CNS) levels. In the present study, we used low Vitamin D dietary intake in mice and evaluated possible changes in gut microbiota, pain processing and endocannabinoid system signaling.Vitamin D deficiency induced a lower microbial diversity characterized by an increase in Firmicutes and a decrease in Verrucomicrobia and Bacteroidetes. Concurrently, vitamin D deficient mice showed tactile allodynia associated with neuronal hyperexcitability and alterations of endocannabinoid system members (endogenous mediators and their receptors) at the spinal cord level. Changes in endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were also observed in the duodenum and colon.Remarkably, the anti-inflammatory anandamide congener, palmitoylethanolamide, counteracted both the pain behaviour and spinal biochemical changes in vitamin D deficient mice, whilst increasing the levels of Akkermansia, Eubacterium and Enterobacteriaceae, as compared with vehicle-treated mice. Finally, induction of spared nerve injury in normal or vitamin D deficient mice was not accompanied by changes in gut microbiota composition.Our data suggest the existence of a link between Vitamin D deficiency – with related changes in gut bacterial composition – and altered nociception, possibly via molecular mechanisms involving the endocannabinoid and related mediator signaling systems.     

Cannabinoid signalling regulates inflammation and energy balance: the importance of the brain-gut axis

Energy balance is controlled by centres of the brain which receive important inputs from the gastrointestinal tract, liver, pancreas, adipose tissue and skeletal muscle, mediated by many different signalling molecules. Obesity occurs when control of energy intake is not matched by the degree of energy expenditure. Obesity is not only a state of disordered energy balance it is also characterized by systemic inflammation. Systemic inflammation is triggered by the leakage of bacterial lipopolysaccharide through changes in intestinal permeability. The endocannabinoid system, consisting of the cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes, plays vital roles in the control of energy balance, the control of intestinal permeability and immunity. In this review we will discuss how the endocannabinoid system, intestinal microbiota and the brain-gut axis are involved in the regulation of energy balance and the development of obesity-associated systemic inflammation. Through direct and indirect actions throughout the body, the endocannabinoid system controls the development of obesity and its inflammatory complications.     

Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain

Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impacts on cognitive functions. Exploration of the therapeutic potential of cannabis-based medicines and synthetic cannabinoid compounds has given us much insight into the physiological roles of endogenous ligands (endocannabinoids) and their receptors. In this article, we examine human longitudinal cohort studies that document the long-term influence of prenatal exposure to cannabis, followed by an overview of the molecular composition of the endocannabinoid system and the temporal and spatial changes in their expression during brain development. How endocannabinoid signaling modulates fundamental developmental processes such as cell proliferation, neurogenesis, migration and axonal pathfinding are also summarized.     

Endocannabinoids: Some Like it Fat (and Sweet Too)

There is growing interest in the commercialisation of the CB₁ receptor antagonist Rimonabant in Europe for the treatment of obesity and the metabolic syndrome. Clinical trials have shown that CB₁ receptor blockers are able to reduce not only food intake but also abdominal adiposity and its metabolic sequelae. Accordingly, CB₁ receptors, and tissue concentrations of endocannabinoids sufficient to activate them, are present in all brain and peripheral organs involved in the control of energy balance, including the hypothalamus, nucleus accumbens, pancreas, adipose tissue, skeletal muscle and liver. At the central level, the endocannabinoid system seems to play a dual role in the regulation of food intake by hedonic and homeostatic energy regulation. At the peripheral level, the endocannabinoid system seems to behave as a system that reduces energy expenditure and directs energy balance towards energy storage into fat. The emerging role of the endocannabinoid system in energy balance at both central and peripheral levels will be discussed in this review.     

Adaptations in endocannabinoid signaling in response to repeated homotypic stress: a novel mechanism for stress habituation

Daily life stressors are a major environmental factor contributing to precipitation and exacerbation of mental illness. Animal models using repeated homotypic stress induce anxious and depressive phenotypes and are used to study the pathophysiology of affective disorders. Here we discuss data demonstrating that repeated homotypic stress produces temporally and anatomically distinct changes in endocannabinoid signaling components within stress-responsive brain regions. We also present evidence describing the neural and behavioral correlates of these adaptations in endocannabinoid signaling. These data support a role for endocannabinoid signaling in the central nervous system response to chronic, homotypic stress, and specifically in the process of stress–response habituation. The clinical implications of these findings for the pathophysiology and treatment of affective disorders are discussed.