脑微透析技术在脑内研究中的应用

脑微透析技术可用于采样脑内神经递质、神经蛋白和激素,并结合高灵敏度的微量化学分析技术对其进行定量分析,从而研究与中枢神经递质相关的疾病、病理及治疗方法等。本文介绍了脑微透析技术的基本原理和过程,并对其在中枢神经递质如兴奋性氨基酸、乙酰胆碱、多巴胺、五羟色胺等及相关药物如选择性五羟色胺再摄取抑制剂、自由基清除剂研究中的应用进行综述。     

Diffuse traumatic brain injury and the sensory brain

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Ethanol-induced hyponatremia augments brain edema after traumatic brain injury

Alcohol consumption augments brain edema by expression of brain aquaporin-4 after traumatic brain injury. However, how ethanol induces brain aquaporin-4 expression remains unclear. Aquaporin-4 can operate with some of ion channels and transporters. Therefore, we hypothesized that ethanol may affect electrolytes through regulating ion channels, leading to express aquaporin-4. To clarify the hypothesis, we examined role of AQP4 expression in ethanol-induced brain edema and changes of electrolyte levels after traumatic brain injury in the rat. In the rat traumatic brain injury model, ethanol administration reduced sodium ion concentration in blood significantly 24 hr after injury. An aquaporin-4 inhibitor recovered sodium ion concentration in blood to normal. We observed low sodium ion concentration in blood and the increase of brain aquaporin-4 in cadaver with traumatic brain injury. Therefore, ethanol increases brain edema by the increase of aquaporin-4 expression with hyponatremia after traumatic brain injury.     

重型颅脑外伤后二次脑损伤相关因素临床观察

目的：探讨引起重型颅脑外伤二次脑损伤的相关因素。方法：回顾性分析2004年6月～2009年6月本科治疗的重型颅脑损伤168例患者的临床资料;比较死亡组与存活组的WBC计数、体温、血压、血糖、血钠水平差异。结果：168例患者死亡49例（29.17%）;两组比较死亡组WBC计数、体温、血糖、血钠水平高,血压低。结论：影响重型颅脑损伤预后二次损伤因素较多,应高度重视监测和严格控制二次脑损伤相关因素。     

Barrier mechanisms in the brain, II. Immature brain

1. It is widely believed that 'the' blood-brain barrier is immature in foetuses and newborns. 2. Much evidence in support of this belief is based on experiments that were unphysiological and likely to have disrupted fragile blood vessels of the developing brain. Some confusion about barrier development arises from insufficient recognition that the term 'blood-brain barrier' describes a complex series of mechanisms controlling the internal environment of the brain. 3. We present evidence showing that the brain develops within an environment that, particularly with respect to protein, is different from that of the rest of the body and that possesses a number of unique features not present in the adult. 4. Barriers to protein at blood-brain and blood-cerebrospinal fluid (CSF) interfaces (tight junctions) are present from very early in development; immunocytochemical and permeability data show that proteins are largely excluded from extracellular space in developing brain. 5. Cerebrospinal fluid in developing brain contains high concentrations of proteins largely derived from plasma. This protein is transferred from blood by an intracellular mechanism across the epithelial cells of the immature choroid plexus. Only a small proportion of choroid plexus cells is involved. The route is an intracellular system of tubulo-endoplasmic reticulum continuously connected across the epithelial cells only early in brain development. 6. High concentrations of proteins in CSF in developing brain are largely excluded from the brain's extracellular space by barriers at the internal and external CSF-brain interfaces. These consist of membrane specializations between surfaces of cells forming these interfaces (neuroependyma on the inner surface; radial glial end feet on the outer surface). In contrast with tight junctions present at the blood-brain and blood-CSF barriers, at the CSF-brain barriers of the immature brain, other junctional types are involved: strap junctions in the neuroependyma and a mixture of junctions at the outer CSF-brain barrier (plate junctions, strap junctions and wafer junctions). These barriers are not present in the adult. 7. Permeability to small lipid-insoluble molecules is greater in developing brain; more specific mechanisms, such as those involved in transfer of ions and amino acids, develop sequentially as the brain grows.     

Barrier mechanisms in the brain, I. Adult brain

1. The adult brain functions within a well-controlled (internal) environment that is separate from that of the internal environment of the rest of the body as a whole. 2. The underlying mechanism of control of the brain's internal environment lies in the presence of tight junctions between the cerebral endothelial cells at the blood-brain interface (blood-brain barrier) and between choroid plexus epithelial cells (blood-cerebrospinal fluid (CSF) barrier). 3. The effect of tight junctions at the blood-brain and blood-CSF barriers is to convert the properties of the individual endothelial and epithelial cells into properties of these interfaces as a whole. 4. Superimposed on the diffusion restriction provided by the tight junctions in the blood-brain and blood-CSF barriers is a series of transport mechanisms into and out of the brain and CSF that determine and control the internal environment of the brain with respect to a wide range of molecules, such as electrolytes, amino acids, glucose, vitamins and peptides. 5. The physical characteristics of drugs, together with their interaction with the properties of the barriers between blood, brain and CSF, determine the extent to which drugs penetrate into the brain. 6. Drugs can be targeted to the brain by making use of knowledge of this interaction between the physical properties of a drug (which can be modified by manipulation of the structure of the molecule in predictable ways) and the influx/efflux mechanisms present in the blood-CSF and blood-brain interfaces.     

孕酮对缺氧缺血性脑损伤新生大鼠血脑屏障通透性及脑水肿的影响

目的研究孕酮(PROG)对缺氧缺血性脑损伤(HIBD)新生大鼠血脑屏障(BBB)通透性和脑水肿的作用,并进一步探讨其潜在的机制。方法 7 d龄SD大鼠96只,随机分成4组:正常组、假手术组、缺氧缺血(HI)组和PROG组。建立HIBD动物模型,HI后24 h,伊文思蓝示踪剂检测BBB;干/湿法测定脑含水量;免疫组织化学法观察大脑皮质水孔通道蛋白4(AQP4)表达。结果正常组和假手术组BBB通透性、脑含水量和脑皮质AQP4的表达差异无显著性(P>0.05);HI组BBB通透性、脑含水量和脑皮质AQP4的表达明显高于假手术组(P<0.01);PROG组BBB通透性、脑含水量和脑皮质AQP4的表达明显低于HI组(P<0.05)。结论 PROG通过减轻BBB破坏和脑水肿对HIBD新生大鼠起脑保护作用,PROG的脑保护作用可能与下调新生大鼠脑皮质AQP4的表达有关。     

亚低温治疗新生兔缺氧缺血性脑损伤脑温监测的研究

目的探讨缺氧缺血性脑损伤（HIBD）新生兔头皮温度与颅内温度之间的关系。方法选择HIBD模型动物12只，作为探针动物。将探针动物置于亚低温治疗仪内，在降温过程中，监测从初始温度（35℃）开始降温达到不同颅内温度的时间和相应的头皮温度，并进行分析。结果颅内温度从35℃降至28℃所需的平均时间为37．5min，头颅温度与头皮温度呈良好的直线正相关关系（r=0．934，P〈0．05）。结论在一定的温度范围内，实验动物头皮温度与颅内温度有较强的直线正相关关系，可通过对头皮温度的测定，间接推断动物的颅内温度。     

Physiological control of brain catechol synthesis by brain tyrosine concentration.

Treatments that raise or lower brain tyrosine concentrations in rats cause parallel changes in the rates at which their brains accumulate DOPA (after aromatic L-amino acid decarboxylase is inhibited by RO4-4602). When the neutral amino acid drug ρ-chlorophenylalanine (PCPA) was injected i.p. into rats (100mg/kg), it decreased brain tyrosine concentrations over a wide range, partly by competing with tyrosine for uptake into the brain. Brain DOPA accumulation after RO4-4602 decreased in parallel. At this dosage, PCPA did not inhibit tyrosine hydroxylase activity in vivo, and, at very high concentrations (10^?3 M) in vitro, it inhibited the enzyme only slightly. Hence, the decrease in DOPA accumulation probably derived from a decrease in the availability of tyrosine (the substrate for tyrosine hydroxylase) rather than from a change in enzyme activity. Similarly, the neutral amino acids, valine and isoleucine (which have been used previously to modify brain tyrosine concentrations and, hence, catechol synthesis), had no effect on tyrosine hydroxylase activity in vitro in concentrations up to 10^?3 M. At high concentrations (10^?3 M), leucine slightly inhibited the enzyme. When rats ingested a single meal containing 40 per cent casein, their brain evidenced increases in both tyrosine levels and catechol synthesis. Thus, the availability of tyrosine to the brain may be one of the factors normally controlling brain catecholamine synthesis.     

脑转移瘤放疗相关认知损害

目的观察脑转移癌患者全脑放疗前后认知功能损害情况。方法用MMSE作为认知评估工具,脑转移癌患者全脑放疗前1周、后1周、放疗后1月,以后每月做认知评估,观察放疗前与放疗后、有症状放疗与无症状放疗认知改变。结果共人组患者41例,基线MMSE评分与放疗后1周比较差异显著[（28．146±0．528）掷（27．585±0．290）,P=0．006]其中放疗前无神经系统症状8例,放疗后4月MMSE减低最明显,其后有所提高,基线MMSE与放疗后4月比较差异显著[（29．125±0．579）vs（26．500±0．524）,P〈0．001）],差异显著;有神经系统症状组其中8例基线MMSE评分≤26,放疗后随着颅内病灶控制MMSE有所提高,放疗后4月提高最明显,基线MMSE与放疗后4月比较差异显著[（25．000±0．524）vs（27．500±0．370）,P=0．001]。结论全脑放疗对认知功能有损害,其损害是缓慢的病理过程,放疗后4月左右认知功能损害最明显,其后有所恢复;同时颅内病灶也对认知功能有影响。     

水通道蛋白-4在兔脑爆炸伤后脑组织中的表达

目的通过建立兔脑爆炸伤模型,研究爆炸后脑组织水通道蛋白-4(AQP-4)的表达情况,探讨爆炸伤后脑水肿的形成机制。方法将新西兰大白兔80只,随机分为对照组和外伤组,其中对照组10只。用纸雷管爆炸制作兔脑爆炸伤模型。外伤组分别随机分为伤后1 h、6 h、12 h、24 h、72 h、7 d、14 d 7组,每组10只。采用免疫组织化学及Western blotting检测AQP-4的表达。结果各组致伤动物脑组织皮层均有不同程度AQP-4表达,广泛分布于星形胶质细胞膜及周围突起,随着伤后时间的推移,AQP-4阳性表达逐渐增强,3 d后表达最明显,7 d后开始下调,14 d仍有较明显表达,各组对比,差异有统计学意义(P<0.05);外伤组与对照组对比各时相点AQP-4阳性表达,均高于对照组(P<0.05)。结论 AQP-4的表达与爆炸性脑损伤引起的继发性脑水肿密切相关。     

Blood–brain barrier, brain metabolism and cerebral blood flow

For optimal function of the brain with its meticulous operations, an adequate and constant micro environment seems to be a prerequisite. This is secured by the blood–brain barrier which is impermeable to hydrophilic substances, with notable exceptions such as glucose, which cross the barrier by a mechanism of facilitated diffusion. A constant micro environment is further secured by the blood flow which is balanced to the metabolic demand of the cerebral tissue and which also contributes to the maintenance of a constant pH. During activation, blood flow and glucose consumption increase more than oxygen consumption in activated areas of the brain. The flow increase forms the physiological basis for measurement and mapping of functional activation using positron emission tomography and the changes in the metabolic pattern which has been called uncoupling of flow and oxygen metabolism is the basis for such measurements using functional magnetic resonance imaging.     

Selective drug delivery approaches to lesioned brain through blood brain barrier disruption

Introduction: The development of therapeutics for central nervous system (CNS) disorders is still considered a challenging area in drug development due to insufficient translocation through the blood-brain barrier (BBB). Under normal conditions, BBB restrict the penetration of more than 98% of blood-borne molecules including drugs to the CNS. However, recent research findings have proven that the nature of the BBB is altered in several neurological conditions. This complexity encourages revisiting drug delivery strategies to the CNS as this can give a wide range of opportunities for CNS drug development.

Areas covered: This review focuses on nanotechnology-based drug delivery platforms designed for selective recruitment into the lesioned brain by taking advantages of BBB disruption that is associated with certain neurological conditions.

Expert opinion: Current CNS therapeutic strategies do not fully address the pathophysiological adaptation of BBB in their design. The lack of selective delivery to the brain lesions has been the culprit behind the failure of many CNS therapeutics. This highlighted the need for smart designs of advanced drug delivery systems that take advantage of BBB structural changes in CNS diseases. Recently, promising examples have been reported in this area, however, more work is still required beyond the preclinical testing.     

重度颅脑创伤后血浆脑钠肽浓度的变化

目的探讨重度颅脑创伤(TBI)后血浆脑钠肽(BNP)浓度的变化。方法选取30例重度TBI患者(TBI组)和10例健康志愿者(对照组),应用免疫放射分析技术测定患者伤后1-2、4-5、7-8和10-11d共4个时间段血浆BNP浓度。结果 TBI患者伤后初始BNP浓度较对照组可升高7.3倍(P<0.01)。弥散性蛛网膜下腔出血(SAH)组BNP浓度在伤后7-8d内较无或仅少量SAH患者增高,颅高压组BNP浓度高于颅内压正常患者(P<0.01)。结论血浆BNP浓度在伤后即迅速升高,且在广泛SAH或颅内压增高患者中可持续升高;血浆BNP浓度升高与不良预后密切相关。     

The changes of plasma brain natriuretic peptide after severe traumatic brain injury

目的 探讨重度颅脑创伤(TBI)后血浆脑钠肽(BNP)浓度的变化.方法 选取30例重度TBI患者(TBI组)和10例健康志愿者(对照组),应用免疫放射分析技术测定患者伤后1-2、4-5、7-8和10-11d共4个时间段血浆BNP浓度.结果 TBI患者伤后初始BNP浓度较对照组可升高7.3倍(P＜0.01).弥散性蛛网膜下腔出血(SAH)组BNP浓度在伤后7-8d内较无或仅少量SAH患者增高,颅高压组BNP浓度高于颅内压正常患者(P＜0.01).结论 血浆BNP浓度在伤后即迅速升高,且在广泛SAH或颅内压增高患者中可持续升高;血浆BNP浓度升高与不良预后密切相关.     

脑损伤过程中血脑屏障通透性的变化及其调节机制

血脑屏障是由脑微血管内皮细胞、星形神经胶质细胞、外膜细胞、血管周围巨噬细胞和基底膜组成的一个复杂系统,对维持中枢神经系统的正常功能非常重要。脑损伤如脑缺血、脑缺氧、脑外伤和蛛网膜下腔出血过程中伴随血脑屏障通透性的变化。脑缺血及其再灌注后可通过花生四烯酸代谢途径、嘌呤核苷酸代谢途径及一氧化氮途径产生自由基,可能是血脑屏障通透性增加的重要机制。血脑屏障的破坏可加重脑损伤程度;脑血管疾病时,保护血脑屏障的完整性可能是减轻脑损伤的重要措施。