氯化锂-匹鲁卡品慢性点燃模型脑中腺苷受体表达失衡的动态研究

目的 探讨慢性点燃癫癎大鼠脑内腺苷受体A1(AIR)及A2a(A2aR)表达的动态演变,评价腺苷受体表达改变在癫癎发病机制中的作用.方法 选用氯化锂-匹鲁卡品慢性点燃小鼠模型,分为模型组、对照组和正常组.采用逆转录PCR(RT-PCR)、免疫荧光及Western blot监测发作后24 h,1、6个月时,脑内AlR、A2aR表达的动态改变.结果 点燃后24 h,小鼠脑内A1R表达增高[受体mRNA(1.1483±0.1182);Western blot(0.7872±0.0621);免疫荧光阳性细胞(76.17±4.62)个/高倍镜视野],A2aR表达降低[受体mRNA(0.8338±0.0572);Western blot(0.2098±0.0257);免疫荧光阳性细胞(43.83.4-5.12)个/高倍镜视野],与正常组及对照组比较差异均有统计学意义(P<0.05).在点燃后1个月、6个月时,A1R表达较点燃前下降,A2aR则明显增高,差异亦具有统计学意义(P<0.01);Jg与1个月时比较,6个月时A1R表达更低[受体mRNA(0.5682±0.0443);Western blot(0.7749±0.0262);免疫荧光阳性细胞(38.50±4.81)个/高倍镜视野],A2aR表达更高[受体mRNA(1.2169 ±0.0332);Western blot(0.7080±0.0371);免疫荧光阳性细胞(114.50 ±4.04)个/高倍镜视野],即慢性期A1R表达降低,A2aR表达增高,且随时间延长越来越明显(t=-19.02-13.28,P<0.05).结论 腺苷受体表达失衡在点燃过程中呈现双向改变特征,急性期适应性调整以最大限度抑制癫癎发作,慢性反复发作则导致A1R及A2aR的表达失衡,可能是导致癫癎发作无法控制的重要因素.     

腺苷2A受体、亲代谢谷氨酸受体对异动症可塑性改变的影响

腺苷2A受体(A2AR)大量分布于脑基底节区,和多巴胺D2受体(D2R)及亲代谢型谷氨酸受体(mGluR5)形成异聚体,共同调节纹状体突触前后功能。研究显示左旋多巴诱发异动症PD动物模型纹状体A2AR、mGluR5表达增加,而两受体拮抗剂应用可改善异动症PD动物模型异常行为,从而提出A2AR和mGlu5参与了异动症突触可塑性的改变。     

溶栓前A2b受体水平与脑缺血出血转化的关系研究

目的 探讨腺苷A2b受体在急性脑缺血溶栓治疗后发生出血转化(hemorrhagic transformation,HT)中的应用价值。方法 收集2015年1月-2017年3月就诊于本院的缺血性脑卒中患者83例,治疗后根据CT和MRI复查表现分为HT组和非HT组,比较2组患者外周血单个核细胞腺苷A2b受体mRNA的表达情况,分析其对脑缺血溶栓治疗后发生HT的预测价值,经logistic回归分析脑缺血溶栓治疗后发生HT的危险因素,比较HT组和非HT组治疗后不同腺苷A2b受体mRNA表达水平患者的NIHSS评分。结果(1)经溶栓治疗后CT和MRI检查显示发生HT者有36例,占43.4%;(2)HT组患者外周血单个核细胞腺苷A2b受体mRNA的表达水平(0.83±0.19)明显高于非HT组(0.49±0.21),利用ROC曲线分析腺苷A2b受体预测脑缺血患者经溶栓治疗后发生HT的预测值为0.63,此时AUC=0.716, 95%CI=0.628～0.837,P<0.001;(3)经多因素非条件Logistic回归分析显示,腺苷A2b受体表达水平是脑缺血患者经溶栓治疗后发生HT的独立危险因素(OR=0.916, 95%CI=0.899～0.969,P=0.032);(4)经溶栓治疗后HT组中腺苷A2b受体>0.63的NIHSS评分最高,而非HT组腺苷A2b受体<0.63的NIHSS评分最低。结论 腺苷A2b受体表达水平是脑缺血患者经溶栓治疗后发生HT的独立危险因素,对患者经溶栓治疗后发生HT具有预测价值。     

腺苷A2A受体拮抗剂改善帕金森病运动并发症

目的 探讨腺苷A2A受体拮抗剂8-(3-Chlorostyryl)caffeine(CSC)对左旋多巴诱发的运动并发症的行为学与细胞学影响.方法 通过6-羟基多巴(6-OHDA)立体定向注射至大鼠前脑内侧束建立帕金森病(PD)动物模型.模型成功大鼠接受每日2次左旋多巴甲酯(50 mg/kg加12.5mg/kg苄丝肼)腹腔注射,持续22 d.在第23天,运动并发症模型组大鼠(n=8)继续接受如上用药,用药组(n=8)在左旋多巴注射前注射腺苷A2A受体拮抗剂CSC,均用药至第29天.同时设假手术组(n=8)和PD对照组(n=8).评估旋转时间,并采用免疫组织化学法和蛋白印迹法观察和检测纹状体区腺苷A2A受体的表达情况.结果 左旋多巴长期用药诱发PD大鼠模型旋转反应时间缩短,同时模型组损伤侧纹状体区腺苷A2A受体的表达升高[阳性细胞指数(IOD),(11.55±2.75)×104>],较假手术组[IOD,(6.02±1.29)×10±]和PD组[IOD,(5.60±1.83)×10±]有统计学意义(F=33.31,P<0.05).CSC用药逆转了左旋多巴诱导的PD大鼠旋转时间的缩短,损伤侧纹状体区腺苷A2A受体的表达[IOD,(5.80±1.56)×104>]也下调至对照组和PD组水平.结论 腺苷A2A受体参与了左旋多巴诱发的运动并发症的发生,腺苷A2A受体拮抗剂可能是治疗PD运动并发症有前景的药物.     

腺苷及其受体在脑损伤中的作用

内源性腺苷具有多种生物活性,通过细胞膜表面的A_1、A_2受体发挥作用,可抑制多种神经递质释放及抑制神经元的激活,并能扩张血管、抑制血小板凝聚、减轻中性粒细胞介导的血 管内膜损伤。腺苷及调节腺苷代谢、腺苷受体活性的药物,可为脑缺血、脑外伤及癫痫的治疗提供新的疗法。     

腺苷及其受体与缺血性脑血管病

自本世纪 2 0年代 ,Drury和 Szent- gyorgy发现腺苷和腺苷酸对心脏的抑制作用以来 ,人们逐渐发现了腺苷和心血管、免疫、肾功能等的关系。随着电生理及药理学研究 ,证实了腺苷受体存在 ,并发现了高亲和力的激动剂和拮抗剂。近年来 ,腺苷作为脑内的一种重要活性物质 ,与缺血性脑血管病的关系逐渐受到重视。本文就近年来腺苷及其受体在脑缺血中作用机制的研究进展作一综述。1　腺苷与腺苷受体　　腺苷是中枢神经系统的一种抑制性神经调质 ,可在大脑的能量储存及能量需求之间提供信号 ,使之达到一种平衡。在正常情况下 ,细胞外腺苷浓度维持在 …     

腺苷A2b受体在大鼠脑缺血再灌注后的表达特点

目的探讨缺血/再灌注(I/R)后脑内腺苷A2b受体(A2bR)表达水平和分布的特点。方法 SD大鼠建立大脑中动脉缺血模型,免疫荧光法检测I/R后A2bR在脑内表达的部位及细胞类型,Western blot检测A2bR表达的相对水平。结果 Western blot结果显示大鼠缺血侧皮质、纹状体及海马区域A2bR表达均较对侧(非缺血侧)显著增高(P 0. 05)。免疫荧光结果显示I/R后腺苷A2bR在神经元、血管内皮细胞和星形胶质细胞表达显著激活。结论 I/R可诱导腺苷A2bR在缺血侧皮质、纹状体及海马区域的神经元、血管内皮细胞和星形胶质细胞表达。     

Istradefylline将是治疗帕金森病的新型药物

KW 60 0 2 (Istradefylline)是选择性腺苷A2A受体 (A2AR)阻断剂 ,通过对纹状体苍白球通路的双重调节作用 ,逆转基底节直接通路和间接通路的失衡 ,改善帕金森病的运动困难、延长左旋多巴作用时间 ,但不增加异动症。KW 60 0 2对黑质多巴胺能神经元有神经保护作用。经临床试验证实 ,KW 60 0 2是有效治疗帕金森病的新型药物     

腺苷及其受体在睡眠剥夺快速抗抑郁效应机制中的研究进展

腺苷是腺嘌呤核苷酸的前体和代谢产物,它通过激活不同亚型的受体,参与睡眠、学习记忆、情绪等多方面的调节。国内外研究表明睡眠剥夺过程中腺苷及其受体发生了一系列变化,而现已明确睡眠剥夺有快速抗抑郁效应,这提示腺苷系统可能在抑郁症病理生理、睡眠剥夺快速抗抑郁效应的机制、疗效等方面有一定作用。本文就腺苷在抑郁症、睡眠剥夺方面的相关研究做一回顾。     

3-硝基丙酸预处理对老龄鼠神经元缺氧耐受性的影响

目的 :研究 3-硝基丙酸 (3- NPA)预处理对老龄鼠神经元缺氧耐受性的影响及其腺苷受体相关机制。方法 :成年和老龄小鼠经 3- NPA预处理后 ,记录海马脑片 CA1区神经元群峰电位波幅 (PSA)在缺氧和恢复供氧后的变化和选择性腺苷 A1 受体激动剂和拮抗剂对 PSA缺氧后恢复的影响。结果 :成年鼠 3- NPA预处理后海马 CA1区神经元 PSA缺氧后恢复由对照组的 2 6 .1± 12 .2 %增至 92 .9± 15 .3%(P<0 .0 1) ,老龄鼠由 17.2± 9.6 %仅增至 5 3.5± 11.5 %(与对照组比较 P<0 .0 5 ,与成年 3- NPA组比较 P<0 .0 5 )。腺苷 A1 受体激动剂 N6-环戊腺苷灌流脑片可模拟 3- NPA产生预处理类似作用 ,促进 PSA缺氧后恢复 ,其神经保护作用同样呈年龄依赖模式 ;A1 受体拮抗剂 8-环戊基 - 1,3-二丙基黄嘌呤可完全抑制 3- NPA预处理导致的 PSA缺氧后恢复的增高。结论 :3- NPA在成年和老年小鼠均可诱导神经元缺氧耐受性的增高 ,其神经保护作用受老龄因素的影响而减弱。腺苷 A1 受体激活参与 3- NPA预处理过程 ,并与年龄差异的形成有关。     

Denervation study of synapses of organ of corti of old world monkeys

Fine structural characteristics of synapses in the spiral organ of Corti were examined, with reference to differences between inner and outer haircell systems, and to location of neurons of origin of efferent axons. Surgical interruption of crossed olivocochlear bundle, of vestibular nerve, of facial nerve, and excision of superior cervical ganglia were used to determine the pathways of efferent axons. Interruption of the vestibular nerve near the brainstem results in degeneration of all efferent terminals on outer hair cells. Mid-line lesions at, and caudal to, the facial colliculus result in degeneration of about half of these efferent terminals. Efferent synaptic bulbs to the inner hair-cell system are small, of the order of one micron, and form type 2 junctions with afferent dendrites. They tend to have more large dense-core vesicles (about 80 nm) than the large efferent terminals of the outer hair-cell system, and appear to be the terminals of axons in the habenula perforata, which exhibit varicosities laden with large dense core vesicles. The varicosities are unaffected by excision of the superior cervical ganglia. So far as our material can reveal, it appears that the varicosities in the habenula perforata do not survive vestibular root interruption, nor do the efferent processes in the internal spiral bundle or at the base of inner hair cells. Most interestingly, the afferent processes of the inner hair-cell system, as identified for example by their relation to pre-synaptic bodies in the inner hair cells, are subject to a trans-synaptic reaction after severance of the vestibular root. They undergo a dramatic cytological transformation, characterized by increase of volume, engorgement with microtubules, microfilaments, microvesicles of various sizes, and clusters of lysosomes. Thus, both the efferent and afferent terminals of the inner hair-cell system show marked cytological differences from the corresponding terminals of the outer hair cell system.     

Mechanism of action of tubocurarine on nicotinic cholinoreceptors of neurons of the sympathetic ganglia of rats

Tubocurarine (Tc) effect on membrane currents elicited by acetylcholine (ACh) was studied in isolated superior cervical ganglion neurons of rat using patch-clamp method in the whole-cell recording mode. The "use-dependent" block of ACh current by Tc was revealed in the experiments with ACh applications, indicating that Tc blocked the channels opened by ACh. Mean lifetime of Tc-open channel complex, tau, was found to be 9.8 +/- 0.5 s (n = 7) at -50 mV and 20-24 degrees C. tau exponentially increased with membrane hyperpolarization (e-fold change in tau corresponded to the membrane potential shift by 61 mV). Inhibition of the ACh-induced current by Tc (3-30 microM/1) was completely abolished by membrane depolarization to the level of 80-100 mV. Inhibition of ACh-induced current was augmented at increased ACh doses. It is concluded that the open channel block produced by Tc is likely to be the only mechanism for Tc action on nicotinic acetylcholine receptors in superior cervical ganglion neurons of rat.     

The effect of age of onset of PD on risk of dementia

Background Dementia occurs in the majority of patients with Parkinson’s disease (PD). Late onset of PD has been reported to be associated with a higher risk for dementia. However, age at onset (AAO) and age at baseline assessment are often correlated. The aim of this study was to explore whether AAO of PD symptoms is a risk factor for dementia independent of the general effect of age. Methods Two community-based studies of PD in New York (n = 281) and Rogaland county, Norway (n = 227) and two population-based groups of healthy elderly from New York (n = 180) and Odense, Denmark (n = 2414) were followed prospectively for 3–4 years and assessed for dementia according to DSM-IIIR. All PD and control cases underwent neurological examination and were followed with neurological and neuropsychological assessments. We used Cox proportional hazards regression based on three different time scales to explore the effect of AAO of PD on risk of dementia, adjusting for age at baseline and other demographic and clinical variables. Findings In both PD groups and in the pooled analyses, there was a significant effect of age at baseline assessment on the time to develop dementia, but there was no effect of AAO independent of age itself. Consistent with these results, there was no increased relative effect of age on the time to develop dementia in PD cases compared with controls. Interpretation This study shows that it is the general effect of age, rather than AAO that is associated with incident dementia in subjects with PD. Received in revised form: 22 December 2005     

Limits of deinstitutionalization--perspectives of relatives of psychiatric patients

After a hopeful beginning, the social process of the reintegration of those with severe mental illness has come to a standstill. I am led to wonder whether "the community" really wants to live together with people suffering from severe mental illness, and if so, how closely? As long as the medical treatment of mental illness provided by the general practitioners is fundamentally deficient, as they are not able to prescribe the necessary interventions--such as out-patient psychiatric nursing, and service providers in the out-patient sector are content with offering increasingly intensive forms of care for the less seriously ill at the cost of the Social Welfare System--the reintegration of those with serious mental illness remains an illusion--which is mainly to the benefit of providers of residential care in homes and hostels.     

Sense of coherence as a predictor of subjective state of health: results of 4 years of follow-up of adults

A number of cross-sectional population studies have shown that a strong sense of coherence (SOC) is associated with various aspects of good perceived health. The association does not seem to be entirely attributable to underlying associations of SOC with other variables, such as age or level of education. OBJECTIVE: The aim of the study reported here was to determine whether SOC predicted subjective state of health. METHODS: The study was carried out as a two-way panel mail survey of 1976 individuals with 4 years interval for two collections of data. The statistical method used was multivariate cumulative logistic modeling. Age, initial subjective state of health, initial occupational training level, and initial degree of social integration were included as potential explanatory variables. RESULTS: A strong SOC predicted good health in women and men. CONCLUSIONS: SOC can be interpreted as an autonomous internal resource contributing to a favorable development of subjective state of health. SOC data should, however, be regarded as complementary to and not a substitute for information already known to be associated with increased risk of future ill health.