急性脑梗死重组组织型纤溶酶原激活物静脉溶栓后严重出血性转化研究进展

严重出血性转化是静脉溶栓治疗最危险的并发症。本文对近年来有关静脉溶栓后严重出血性转化的定义、临床表现、影像学特征以及相关危险因素的研究进展进行综述。对具有严重出血性转化高风险的急性脑梗死患者可以选择低剂量重组组织型纤溶酶原激活物(recombinant tissue plasminogen activator,rtPA)静脉溶栓治疗,以降低症状性颅内出血的发生风险。     

单核细胞/高密度脂蛋白比值与急性脑梗死出血性转化和预后的研究

急性脑梗死(AIS)是常见的脑血管病,已成为世界上第三大死亡原因,目前静脉注射重组组织型纤溶酶原激活剂是治疗AIS患者最有效的方法之一.出血性转化是溶栓后的常见并发症,患者的致残率和病死率显著增加.研究表明炎症反应在出血性转化中发挥了重要作用.近年研究发现单核细胞和高密度脂蛋白对AIS的出血性转化和预后有重要影响.文中...     

重视脑梗死的出血性转化

出血性转化(hemorrhagic transformation,HT)是颇令临床医生担心的脑梗死的合并症。据文献报道,出血性转化的发生率尸解资料为29%;系统回顾性荟萃资料显示脑梗死后任何类型的出血性转化发生率在0～85%之间;理论上来说,出血性转化可发生于任何脑梗死患者,可见于脑梗死自然演变病程     

缺血性脑卒中溶栓后出血性转化的研究进展

正组织型纤溶酶原激活剂(tissue-type plasminogen activator,t-PA)溶栓治疗是急性缺血性脑卒中最有效的治疗方法。但t-PA溶栓治疗会显著增加出血性转化(hemorrhagic transformation,HT)的发生率,严重的出血性转化可导致病情急剧恶化,甚至死亡。美国国立神经疾病与卒中研究所在2004年的一项研究表明,脑梗死后3h内应用尿激酶(urokinase,UK)或t-PA治疗后的症状性出血性转化的发生率为     

降纤治疗急性脑梗死后出血性转化的原因及危险因素分析

目的研究降纤治疗急性脑梗死后出血性转化的原因及相关危险因素。方法选取2015-02—2017-02至河南医学高等专科学校附属医院接受降纤治疗的120例急性脑梗死患者为研究对象,按照降纤治疗后是否产生出血性转化分为A组(n=28)与B组(n=92),A组有出血性转化,B组无出血性转化,比较2组临床资料,总结出血性转化相关危险因素。结果 2组年龄、病史、治疗前空腹血小板、收缩压、低密度蛋白、脉压差及纤维蛋白原比较无明显差异(P0.05);A组NIHSS评分、大面积脑梗死率、皮层梗死率、空腹血糖水平、心源性脑栓塞率及治疗前空腹尿酸水平明显高于B组(P0.05);Logistic多因素分析显示,NIHSS评分、大面积脑梗死、心源性脑栓塞属于降纤治疗急性脑梗死后出血性转化主要独立危险因素(P0.05)。结论NIHSS评分、尿酸值、大面积脑梗死、皮层梗死、心源性脑栓塞及空腹血糖高均为降纤治疗急性脑梗死后出血性转化原因,其中心源性脑栓塞、NIHSS评分高及大面积脑梗死属于出血性转化主要独立危险因素。     

脑梗死后出血性转化患者血浆白细胞介素1β、6、10含量的变化

目的观察脑梗死后出血性转化患者血浆IL-1β、IL-6、IL-10的变化,探讨脑梗死出血性转化与脑梗死后炎性反应之间的关系。方法 60例脑梗死并发出血性转化患者按出血严重程度分为HI-1型15例,HI-2型15例,PT-1型15例,PT-2型15例。按年龄、性别、神经功能缺损评分(NIHSS)、出血部位、治疗措施相匹配的原则选取无出血性转化的脑梗死患者作为对照组。分别为:HI-1型对照组15例,HI-2型对照组15例,PT-1型对照组15例,PT-2型对照组15例。测定所有患者入院2 d清晨血浆IL-1β、IL-6、IL-10、S-100β蛋白浓度。结果和相对应的对照组相比出血性转化患者发病初期IL-1β、IL-6浓度显著高于对照组,而IL-10、S-100β蛋白的浓度无明显差别。结论在同样程度脑损伤的情况下,急性期的高水平的促炎性细胞因子IL-1β、IL-6可能是通过炎性反应促进了血脑屏障的破坏和脑梗死后出血性转化的发生。     

影响脑梗死后出血性转化患者预后因素的探讨

目的探讨影响脑梗死后出血性转化患者预后的相关因素。方法运用SPSS13.0统计软件对58例脑梗死后梗死区内出血的患者和58例单纯脑梗死患者的性别、年龄、血压、血糖、血脂、有无颈动脉斑块、有无脑梗死家族史、累及的动脉系统和出入院时美国国立研究院卒中量表(NIHSS)评分差值进行分析。结果两组患者的性别、年龄、血压、血糖、血脂、有无颈动脉斑块、有无脑梗死家族史、累及的动脉系统相比差异无统计学意义;出血性脑梗死组、点状及片状出血性脑梗死组、颈内动脉系统出血性脑梗死组及多个部位出血性脑梗死组的预后与单纯脑梗死组相比差异有统计学意义(均P<0.05);椎-基底动脉系统出血性脑梗死组、单个部位出血脑梗死组与单纯脑梗死组预后的比较差异无统计学意义。结论影响脑梗死出血性转化预后的相关因素主要为出血量、出血部位。     

影响急性脑梗死出血性转化的危险因素

目的 探讨急性脑梗死的出血性转化的危险因素。方法 收集2012年1月～2015年1月在湖北省恩施州利川市人民医院神经内科住院的急性脑梗死患者的临床及实验室检查资料,并在入院后10 d内行头颅CT复查,采用多变量logistic回归分析确定出血性转化的独立危险因素。结果 共纳入345例急性脑梗死患者,其中男205例,女140例,101例发生出血性转化。出血性转化组的年龄、脑梗死体积、脑卒中史或TIA史、高血压病、糖尿病、抗凝药和房颤的比例均显著高于非出血性转化组(P<0.05),而2组抗血小板聚集药、他汀类、高脂血症史、吸烟或饮酒史无明显差异(P>0.05)。多变量logistic回归分析显示年龄(OR=1.168,95%,CI=1.059～3.412; P=0.021)、梗死体积(OR=3.461,95%C1=1.317～6.270; P=0.044)和房颤(OR=1.284,95%C1= 1.117～2.903; P=0.015)为出血性转化的独立危险因素。结论 急性脑梗死患者出血性转化的发生率为29.3%,年龄、脑梗死体积和房颤为出血性转化的独立危险因素,绝大多数出血性转化不会加重临床症状,临床症状加重的患者主要是脑实质血肿型。     

急性缺血性脑卒中出血性转化的发生率

急性缺血性脑卒中按发生原因分为自发性出血性转化和继发性出血性转化。自发性出血性转化即出血性脑梗死,发生率为5%~10%(文献报告)或1.4%~7.3%(多项研究证实)或0~3.4%(汇总分析),溶栓后自发性出血性转化发生率为9%~12%(头颅CT证实)或10.0%~19.8%(多项研究证实),血管介入治疗后自发性出血性转化发生率为8.1%~37.0%,抗血小板聚集治疗和抗凝治疗后自发性出血性转化的发生率分别为4.0%~5.3%,和1.4%~13.0%。     

血浆PPARγ水平对非溶栓急性脑梗死患者出血性转化的诊断性价值研究

目的 探讨非溶栓急性脑梗死患者血浆过氧化物酶体增殖物激活受体γ(PPARγ)水平预测出血性转化的价值.方法 选取2017年5月～2020年5月于本院接受治疗的92例非溶栓急性脑梗死患者为研究对象,根据有无发生出血性转化将其分为出血性转化组14例和未出血性转化组78例.采用酶联免疫吸附(ELISA)法检测血浆PPARγ、...     

Autoradiographic localization of 5HT1 binding sites in the medulla oblongata of the rat.

Serotonin (5HT) binding sites in the medulla oblongata of the rat were localized using autoradiographic techniques with radioactive ligands that express high affinity for the 5HT1 (3H-5HT), 5HT1A (3H-80H-DPAT), or 5HT1B (125I-CYP with isoproterenol) receptor subtypes. 5HT1A sites were concentrated primarily in certain sensory regions of the medulla and in regions that contain serotonergic neurons. 5HT1B sites were diffusely distributed throughout the reticular formation and motor regions as well as being localized to certain sensory regions. A surprising finding was an association of 5HT1B binding sites with the corticospinal tract. 3H-5HT binding generally reflected the combined pattern of 5HT1A and 5HT1B sites but was also extremely dense in the choroid plexus, which exhibited virtually no 5HT1A or 5HT1B ligand binding. Presumably this binding, which was blocked by ketanserin, corresponds to 5HT1C sites. Administration of the serotonergic neurotoxin 5,7-dihydroxytryptamine reduced 5HT1A binding sites in regions of the medulla that contain serotonergic neuronal cell bodies. 5HT1B binding was not significantly altered in any area of the medulla. These studies indicate an important role for 5HT1A ligands in the processing of visceral and somatic sensory information, in regulation of certain cerebellar afferent projections, and in the regulation of serotonergic neuronal activity. 5HT1B ligands would be expected to regulate visceral and somatic efferent activity, as well as sensory information and reticular efferent activity, and might presynaptically regulate cortical inputs to the brain stem and spinal cord.     

Updated overview of the putative role of the serotoninergic system in obsessive-compulsive disorder

The pathophysiology of obsessive-compulsive disorder (OCD) remains unknown. However, increasing attention has been paid to the putative role of the serotoninergic system, the strongest evidence being based on the widely demonstrated efficacy of serotonin (5HT) reuptake inhibitor antidepressants in the treatment of OCD. The therapeutic effects are correlated with changes in peripheral parameters of 5HT function, which have been found to be altered in OCD, suggesting the possibility of reduced 5HT reuptake capacity. This could reflect a compensatory mechanism presumably due to decreased availability of extracellular 5HT, as evidenced by data derived from direct assessment of central 5HT neurotransmission. The development of new neurochemical probes that explore the sensitivity of various 5HT receptor subtypes has provided precious information. m-Chlorophenylpyperazine (m-CPP), an agonist to 5HT1A, 5HT1D, and 5HT2C receptors, and which also blocks 5HT3 receptors, exacerbates OC symptoms. In contrast, neither MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine), a 5HT1A and 5HT2C receptor agonist, nor ipsapirone or buspirone, which acts as an agonist to 5HT1A receptors, have any effect on OC symptom severity. This suggests the potential implication of the 5HT1D receptor, as shown by the aggravation of OC manifestations in response to sumatriptan, a selective 5HT1D receptor agonist. The 5HT3 plays no specific role, given the lack of influence of the 5HT3 antagonist ondansetron, on OC symptom intensity. Further studies are required to elucidate the pharmacological molecular determinants of the putative 5HT1D receptor dysfunction.     

Alpha-methylserotonin, a substitute transmitter for serotonergic neurons.

1. Administration to rats of alpha-methyltryptophan (AMTP) gives rise to alpha-(AM5HT) in the brain along with a decrease of cerebral 5HT. 2. Analysis of fractions prepared from brains of AMTP-injected rats shows that AM5HT occurs mainly in the synaptosomes. 3. The synaptosomal content of AM5HT in proportion to the total AM5HT in the brain represents the same ratio as for the corresponding fractions of 5HT.     

Increased nitric oxide synthase activity in a model of serotonin depletion

Serotonin (5HT) containing cell bodies are localized in mesencephalic and rhombencephalic raphe nuclei. It has been proposed that 5HT could be involved in neuronal development and plasticity. In the central nervous system, nitric oxide (NO) has been postulated as a neurotransmitter and neuromodulator, and has been implicated in neurotoxicity as well as in neuroprotection. Using the nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) technique, NO synthesizing neurons were described in raphe nuclei. By immunohistochemistry, nitric oxide synthase (NOS) was found colocalized with 5HT in some dorsal raphe nucleus (DRN) neurons. In a model of inhibition of 5HT synthesis produced by daily administration of parachlorophenilalanine during 14 days, we have studied the relationship between 5HT and NO systems after 5HT depletion by histochemical and immunocytochemical methods. After the treatment, we observed an important reduction of 5HT immunostaining in the DRN and enhanced NOS activity demonstrated by NADPH-d technique, especially in the dorsomedial and ventromedial subgroups. In spite of the increased NOS activity, we could not observe significant changes in the NOS-immunoreactivity in the DRN after 5HT depletion. These results could indicate that 5HT depletion is concomitant with changes in NOS activity without affecting NOS expression in the DRN.     

Serotonin-mediated striatal dopamine release involves the dopamine uptake site and the serotonin receptor

Modulation of striatal dopamine (DA) release by serotonin (5HT) and its antagonists was studied utilizing in vitro perfusion techniques. In isolated striatal tissue, 5HT (10 microM) increased the fractional basal release of labeled DA. The 5HT(2/1c) antagonist ketanserin (5 microM) also stimulated the basal release. These two effects were mediated by different mechanisms as cocaine (10 microM) greatly inhibited the 5HT-mediated response, but slightly increased the ketanserin-mediated response. 6-Nitroquipazine maleate (10 microM, 5HT uptake inhibitor) partially inhibited both responses. Inhibition by GBR 12909 (DA uptake inhibitor) at 1 microM of the 5HT-mediated DA release was similar to that of cocaine, but at 10 microM it increased release before addition of 5HT, and maintained elevated DA release while present in the incubation medium. At 1 microM GBR 12909, ketanserin-mediated DA release was stimulated and a much greater release was seen at 10 microM, but the prolonged release was not observed as after 5HT-mediated release. Among other antagonists methiothepin (5HT(1,2,6) antagonist) also enhanced DA release, whereas oxymetazoline (5HT(1A,1B,1D) agonist) had no effect. RS2359-190 (5HT(4) antagonist) had a small effect (slight stimulation) on 5HT-mediated DA release, and no effect on ketanserin-mediated DA release. CGS 12066A (5HT(1B) agonist) inhibited 5HT-mediated DA release. The glutamate antagonist MK-801 and the GABA(A) antagonist bicuculline had no affect on either response. These results indicate that 5HT-mediated DA release occurs via reversal of the DA transporter and that inhibitory presynaptic 5HT heteroreceptors and both inhibitory and stimulatory somato-dendritic 5HT receptors regulate release. In addition to the reversal of the transporter, an inhibitory 5HT(2) component was identified.     

Neuronal and inducible nitric oxide synthase immunoreactivity following serotonin depletion

Serotonin (5HT) modulates the development and plasticity of its innervation areas in the central nervous system (CNS). Astrocytic 5HT(1A) receptors are involved in the plastic phenomena by releasing the astroglial-derived neurotrophic factor S-100beta. Several facts have demonstrated that nitric oxide (NO) and the nitric oxide synthase enzyme (NOS) may also be involved in this neuroglial interaction: (i) NO, S-100beta and 5HT are involved in CNS plasticity; (ii) micromolar S-100beta concentration stimulates inducible-NOS (iNOS) expression; (iii) neuronal NOS (nNOS) immunoreactive neurons are functionally and morphologically related to the serotoninergic neurons; (iv) monoamines level, including 5HT, can be modulated by NO release. We have already shown that 5HT depletion increases astroglial S-100beta immunoreactivity, induces neuronal cytoskeletal alterations and produces an astroglial reaction, while once 5HT level is recovered, a sprouting phenomenon occurs [Brain Res. 883 (2000) 1-14]. To further characterize the relationship among nNOS, iNOS and 5HT we have analyzed nNOS and iNOS expression in the CNS after 5HT depletion induced by parachlorophenylalanine (PCPA) treatment. Studies were performed immediately after ending the PCPA treatment and during a recovery period of 35 days. Areas densely innervated by 5HT fibers were studied by means of nNOS and iNOS immunoreactivity as well as NADPH diaphorase (NADPHd) staining. All parameters were quantified by computer-assisted image analysis. Increased nNOS immunoreactivity in striatum and hippocampus as well as increased NADPHd reactivity in the striatum, hippocampus and parietal cortex were found after PCPA treatment. The iNOS immunoreactivity in the corpus callosum increased 14 and 35 days after the end of PCPA treatment. These findings showed that nNOS immunoreactivity and NADPHd activity increased immediately after 5HT depletion evidencing a close functional interaction between nitrergic and serotoninergic systems. However, iNOS immunoreactivity increased when 5HT levels were normalized, which could indicate one of the biological responses to S-100beta release.     

Involvement of serotonin 5HT1 and 5HT2 receptors and nitric oxide synthase in the medial preoptic area on gonadotropin secretion

Due to the stimulatory action of serotonin (5HT) and nitric oxide (NO) on the secretion of gonadotropins and PRL, this work aimed at investigating the participation of serotoninergic receptors 5HT(1) and 5HT(2) of the medial preoptic area (MPOA) in the control of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) secretion and the possible modulation by ovarian steroids as well as the possible participation of NO as a mediator of the stimulatory effects of serotonin in the MPOA on LH secretion. Microinjections of three different doses (0.02, 0.2, and 2 ug) of methiothepin, a serotoninergic 5HT(1) antagonist or ketanserin, a seretoninergic 5HT(2) antagonist, were carried out into the MPOA in ovariectomized rats treated or not with estrogen or estrogen plus progesterone. Other groups of ovariectomized rats treated with estrogen, estrogen plus progesterone or vehicle were prepared to evaluate NOS activity in the MPOA. Plasma LH, FSH, and PRL in ovariectomized rats were not altered by the microinjection of methiothepin or ketanserin in the MPOA. Methiothepin microinjection in the MPOA reduced LH but did not change plasma FSH and PRL in ovariectomized rats treated with estrogen or estrogen plus progesterone. On the other hand, ketanserin microinjection in the MPOA reduced plasma LH and FSH but did not change plasma PRL in the animals submitted to the same steroidal treatment. NOS activity in the MPOA was significantly reduced by methiothepin or ketanserin in ovariectomized rats treated with estrogen or estrogen plus progesterone. In conclusion, this work showed that in the studied conditions, serotonin in the MPOA: (1) does not work in the control of PRL secretion through 5HT(1) and 5HT(2) receptors; (2) integrates the control of FSH secretion by 5HT(2) receptors, but not 5HT(1); (3) in the presence of estrogen, stimulates LH secretion by 5HT(1) and 5HT(2) receptors, which can be differentially modulated by progesterone; (4) at least partly, stimulates LH secretion by nitric oxide activity.     

Central aminopeptidase and serotonin system activities: possible relationship

The co-localization of serotonin (5-hydroxytryptamine, 5HT) and neuroactive peptides in the same neuron points to the importance of interactions between serotonergic and peptidergic systems in maintaining body homeostasis. In this work, we used an original genetic rat model to search for possible interrelations between 5HT system functioning and the activities of aminopeptidases, i.e. enzymes which are the key regulators of (neuro)peptides level/function. The activities of three cytosolic exopeptidases: alanyl aminopeptidase (alanyl-AP), arginyl aminopeptidase (arginyl-AP) and dipeptidyl peptidase III (DPP III) were measured in brains and peripheral tissues of the sublines of rats with constitutionally upregulated/downregulated 5HT transporter activity. These rat sublines, termed as high-5HT and low-5HT subline, have been obtained previously by selective breeding for the extreme values of platelet 5HT level and velocity of 5HT uptake. Besides in the periphery they show marked alterations also in brain 5HT function, indicating the differences in central 5HT transmission/homeostasis. In this study, we have found that animals from the high-5HT subline have significantly lower activity of brain alanyl-AP (p<0.05) and arginyl-AP (p<0.01) as compared to control animals. No other differences were noticed regardless of the 5HT subline, investigated organ or analyzed aminopeptidase. Results suggest that the constitutional upregulation of serotonergic activity may be related to a lowered brain cytosolic aminopeptidase activity which may have an influence on the cleavage of their physiological substrates.     

Serotonergic modulation of intracellular calcium dynamics in neonatal hypoglossal motoneurons from mouse

(1) Serotonin (5HT)-mediated calcium signaling was investigated in hypoglossal motoneurons (HGMs) in brain stem slices of neonatal mice. Electrical activity and associated calcium signaling were studied by simultaneous patch clamp recordings and high resolution calcium imaging. (2) Bath application of 5HT (5-50 microM) depolarized membrane potential of HGMs and generated action potential discharges that were accompanied by elevations in intracellular calcium concentrations ([Ca2+]i) in the soma and dendrites. Current-evoked bursts of action potentials were more intense in the presence of 5HT; however, the corresponding calcium signals were reduced. (3) The 5HT2 receptor agonist alpha-Methyl-5HT (25, 50 microM) had effects on membrane potential, discharge properties and [Ca]i that were identical to those observed for 5HT, whereas the 5HT3 receptor agonist 1-(m-chlorophenyl) biguanide (50 microM) had no effect on membrane properties or intracellular calcium levels. (4) 8-OHDPAT (25, 50 microM), a 5HT1A receptor agonist, was without effect on steady-state membrane potential or basal [Ca]i. Similar to 5HT and alpha-Methyl-5HT, 8-OHDPAT depressed stimulus-evoked calcium transients in current and voltage clamp mode. (5) Our results suggest that calcium profiles in hypoglossal motoneurons are differentially regulated by 5HT1A and 5HT2 receptors. Activation of 5HT1A receptors primarily reduced voltage-activated Ca2+ signals without a significant impact on basal [Ca]i. In contrast, activation of 5HT2 receptors initiated a net inward current followed by membrane depolarization, where the resulting pattern of action potential discharges represents the essential determinant of global elevations in [Ca2+]i. Taken together, our results therefore identify 5HT-dependent signal pathways as a versatile tool to modulate hypoglossal motoneuron excitability under various physiological and pathophysiological conditions.     

Serotonin denervation enhances responsiveness of presynaptic dopamine efflux to acute clozapine in nucleus accumbens but not in caudate-putamen

Clozapine alters mesolimbic dopamine (DA) function but spares nigrostriatal DA function in laboratory animals, but the underlying mechanism is unknown. In the present study, acute intraperitoneal injection of clozapine (5-40 mg/kg) increased extracellular DA levels in nucleus accumbens (Acb) and caudate-putamen (CPu) of awake, freely moving rats as measured by in vivo brain microdialysis, without anatomic selectivity. However, in serotonin (5HT)-denervated rats acute clozapine preferentially enhanced DA levels in Acb as compared to CPu. Since (i) up-regulation of 5HT receptors on DA neurons may result from 5HT denervation, (ii) clozapine has potent anti-5HT action, and (iii) 5HT receptors are more dense in Acb than CPu, these data appear to add additional weight to previous suggestions that a serotonergic mechanism may partly underlie clozapine's mesolimbic selectivity.