苯甲酸雌二醇对慢性脑缺血大鼠海马胆碱乙酰转移酶变化及雌激素的影响

目的观察苯甲酸雌二醇对慢性脑缺血大鼠海马神经元胆碱乙酰转移酶的影响,以探讨胆碱乙酰转移酶的变化在慢性脑缺血发病中的作用及雌二醇对此变化的影响。方法采用双侧颈总动脉永久性结扎制备慢性脑缺血模型,30只大鼠随机分为假手术组、缺血组和雌二醇治疗组。各组于造模60d后,应用Y迷宫观察其行为学改变,采用免疫组化观测大鼠海马神经元胆碱乙酰转移酶的变化。结果治疗组较缺血组认知障碍明显改善（P〈0.01）,其海马胆碱乙酰转移酶的表达也明显增高（P〈0.01）。结论苯甲酸雌二醇能改善慢性脑缺血大鼠的认知功能可能与其提高海马区胆碱乙酰转移酶水平有关。     

丁基苯酞对慢性脑缺血老龄大鼠海马中NMDA受体亚单位NR2B及突触素表达的影响

目的 观察丁基苯酞对慢性脑缺血老龄大鼠海马中N-甲基-D-天门冬氨酸受体2B亚单位(NR2B)及突触素表达的影响.方法 采用免疫组化方法观察丁基苯酞对慢性脑缺血老龄大鼠海马中NR2B及突触素表达的影响.结果 B组与A组比较,海马CA1区、CA3区及齿状回NR2B及突触素的表达明显减少(P＜0.05),C、D组大鼠海马各区NR2B及突触素的表达与单纯缺血组比较均不同程度增加(P＜0.05);D组与C组比较,NR2B及突触素的表达增加更明显(P＜0.05).结论 慢性缺血3个月后,大鼠海马CA1区、CA3区及齿状回中NR2B 及突触素的表达明显减少,而丁基苯酞能改善这种缺血改变,增加NR2B 及突触素的表达.     

电针预处理对脑缺血后突触结构的影响

目的 探讨电针预处理对大鼠脑缺血再灌注损伤后神经元突触可塑性有无影响.方法 采用线栓法制备大鼠大脑中动脉阻塞(MCAO)模型,研究电针预处理对缺血后1 w缺血区皮层神经元突触超微结构、突触素p38、神经生长因子(NFG)的影响.结果 缺血24h和1 w时,缺血对照组和电针组神经功能评分均低于假手术组(P＜0.05),相同时间点电针组评分高于缺血组(P＜0.05).缺血1 w时,缺血对照组和电针组突触的面数密度、突触连接带面密度、突触体密度、突触后致密物质、突触间隙宽度均低于假手术组,电针组上述各参数高于缺血对照组;突触界面曲率三组间无显著差异.缺血对照组和电针组在缺血1 w时突触素p38表达明显低于假手术组,两组间无显著差异;上述两组NGF的免疫阳性细胞数明显高于假手术组,电针组高于缺血对照组.结论 电针预处理可改善大鼠脑缺血1 w后突触超微结构,NGF表达增加可能促进了神经元的突触可塑性.     

慢性脑缺血老龄大鼠海马中突触素的表达特征

目的 研究老龄大鼠慢性脑缺血后大脑海马中突触素表达特征.方法 应用免疫组化染色技术检测大鼠脑海马中CA1区、CA3区和齿状回中突触素的表达.结果 缺血组海马CA1区、CA3区和齿状回三处突触素灰度值均低于对照组,差异有统计学意义(P<0.05.结论 老龄大鼠海马结构内CA1区、CA3区及齿状回内突触素和NR2B的表达明显减少.     

养血清脑颗粒对大鼠慢性脑缺血细胞凋亡及神经细胞突触结构的影响

目的 研究养血清脑颗粒对大鼠慢性脑缺血模型的神经细胞凋亡及突触结构的影响.方法 SD大鼠随机分为假手术对照组、慢性缺血组、慢性缺血+养血清脑颗粒治疗组、慢性缺血+养血清脑颗粒预防组.应用大鼠双侧颈总动脉结扎方法制备慢性脑缺血大鼠模型,应用流式细胞术检测细胞凋亡,透射电镜和图像分析观察并测定大鼠海马及皮质突触的形态参数.结果 流式细胞术显示脑缺血14天后,细胞凋亡明显增多,养血清脑颗粒可明显抑制细胞凋亡;缺血组可导致突触结构参数变化,而慢性缺血+养血清脑颗粒治疗组和慢性缺血+养血清脑颗粒预防组可明显减轻这一变化.结论 养血清脑颗粒对慢性脑缺血细胞凋亡及突触结构改变的抑制作用有可能对慢性脑缺血的病理改变起到预防和治疗的作用.     

PKC、CaMK Ⅱ在慢性脑缺血大鼠认知功能损害中的作用

目的 观察慢性脑缺血大鼠海马组织蛋白激酶C(protein kinase C,PKC)、钙调素依赖蛋白激酶Ⅱ(calmodulin-depend-ent protein kinase Ⅱ,CaMK Ⅱ)水平变化,探讨其在慢性脑缺血认知功能损害中的作用.方法 采用双侧颈总动脉永久性结扎(per-manent occlusion of bilateral common carotid arteries,2-VO)制作慢性脑缺血模型,40只大鼠随机分为假手术组,缺血3周组,缺血8周组,缺血12周组(n=10),Morris水迷宫检测大鼠空间学习记忆能力,Western blot法检测大鼠海马神经元PKC、CaMKⅡ、谷氨酸受体NMDAR1、NMDAR2B的表达水平,并观察其动态变化过程.结果缺血3周组大鼠的空间学习记忆能力较假手术组显著下降(P<0.05),缺血8周和12周组下降更加明显(P<0.01).缺血3周组海马区PKC、CaMKⅡ与谷氨酸受体NMDAR 1、NMDAR 2B表达水平较假手术组增高(P<0.01),缺血8周和12周组表达均降低(P<0.01).结论 PKC、CaMKⅡ与谷氨酸受体NMDAR 1、NMDAR2B变化规律相同,在缺血后期PKC、CaMKⅡ表达减低可能与学习记忆损害有关.     

雌二醇对慢性脑缺血大鼠学习记忆能力及额叶凋亡相关蛋白表达的影响

目的 研究17-β雌二醇对慢性脑缺血大鼠学习记忆能力及额叶Bcl-2、Bax蛋白表达的影响. 方法 双侧颈总动脉结扎法制备前脑缺血致血管性痴呆大鼠模型,将大鼠随机分为假手术组、模型组和治疗组,每组20只,观察雌二醇的保护作用.通过Y-型迷宫测试大鼠学习记忆能力,HE染色观察大鼠额叶皮质神经元的形态变化,免疫组化染色检测Bcl-2、Bax的表达. 结果 模型组与假手术组相比学习记忆能力明显下降(P＜0.01), 皮质Bcl-2、Bax免疫阳性细胞数增加(P＜0.01).17-β雌二醇组与模型组相比学习记忆能力明显改善(P＜0.01),皮质Bcl-2免疫阳性细胞数明显增加(P＜0.01),Bax免疫阳性细胞数明显减少(P＜0.01). 结论 17-β雌二醇可能通过调节Bcl-2、Bax蛋白表达来抑制额叶皮质细胞凋亡,从而改善慢性脑缺血大鼠的记忆能力.     

骨髓间充质干细胞移植对慢性脑缺血大鼠认知功能及海马CA1区EphB2的影响

目的 观察骨髓间充质干细胞移植(mesenchymal stem cells,MSCs)对慢性脑缺血大鼠认知功能及海马CA1区EphB2的影响.方法 将SD大鼠随机分为假手术组、模型组、实验组(2VO模型+MSCs干预),选8、10、12w 3个时间点,采用双侧颈总动脉永久性阻断法(2VO)建立慢性脑缺血模型,通过Morris水迷宫检测各组大鼠的认知功能,同时用免疫组织化学的方法和Western blot检测大鼠海马CA1区EphB2的表达.结果 模型组和实验组大鼠与假手术组相比逃避潜伏期明显延长,在同一时间点实验组逃避潜伏期较模型组明显缩短(P＜0.05),实验组海马CA1区EphB2的表达较模型组增多(P＜0.05).结论 骨髓间充质干细胞移植能明显改善大鼠慢性脑缺血所致的认知功能障碍,其机制可能是通过升高EphB2的表达而改善学习记忆能力.     

PKA-CREB信号转导通路在大鼠慢性脑缺血所致认知功能障碍中的作用

目的:观察PKA-CREB信号转导通路在慢性脑缺血所致大鼠认知功能损害中的作用。方法:结扎大鼠双侧颈总动脉,制成慢性脑缺血模型,分缺血8周组和假手术对照组,术后第8周时用Morris水迷宫测定大鼠学习记忆能力。用Westernbloting检测大鼠海马胞核内PKAca及pCREB的表达。结果:缺血组与假手术组相比学习记忆能力明显下降(P<0.05),缺血组大鼠海马中PKAca及pCREB的表达与假手术组相比也下降(P<0.05),且两者之间的下降存在正相关关系。结论:PKA-CREB信号转导通路可能参与了慢性脑缺血所致大鼠认知功能的损害。     

当归注射液抗慢性脑缺血大鼠认知功能损害的实验研究

目的 观察当归注射液对慢性脑缺血后认知功能改变及氧化应激损伤和胆碱能系统的影响,探讨当归注射液改善慢性脑缺血认知功能的作用及机制. 方法 50只Wistar大鼠采用随机数字表法分为假手术组(n=16)、生理盐水组(n=18)及当归治疗组(n=16),后两组大鼠制成双侧颈动脉结扎慢性脑缺血模型(即2VO模型),缺血4周、干预4周后水迷宫检测3组大鼠认知功能,并取脑皮质测定氧化产物及胆碱酯酶含量. 结果 慢性脑缺血后大鼠的空间记忆能力受损,定位航行实验中第4、5天当归治疗组的隐匿平台逃避潜伏期较假手术组有所增加,但较生理盐水组明显缩短(分别为22.53±1.27、27.67±1.34),3组之间差异有统计学意义(P<0.05);当归治疗组在空间探索试验中穿越平台的次数较生理盐水组增多(分别为1.25±0.78、0.56±0.63),在平台区的停留时间延长(分别为21.99±4.97、12.80±2.88),3组之间差异有统计学意义(P<0.05);当归治疗组AchE含量有所下降,但与假手术组比较差异仍有统计学意义(P<0.05),同时,MDA含量增高,SOD活力、抑制羟自由基能力及总抗氧化能力降低,与假手术组比较差异没有统计学意义(P>0.05). 结论 当归注射液能改善慢性脑缺血的认知功能损害,其作用可能与抑制氧化应激反应有关.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

Pediatric Epilepsy Surgery

Summary: The use of implantable arrays of epidural electrodes has made it possible to carry out extraoperative electrocorticography (ECoG) and functional localization in the awake child. This has permitted cortical excisions that are determined by criteria similar to those obtained during surgical procedures performed under local anesthesia in adults. In addition, the method also permits simultaneous ECoG and video monitoring during the child's symptomatic seizures, providing additional important localizing information that is impractical to obtain in operations under local anesthesia. We report our experience with 75 children, ages 5 months to 15 years, whom we have managed with epidural electrode arrays. The method of extraoperative ECoG is described and illustrative cases are presented to demonstrate its feasibility and utility in children. In addition, we call attention to gliomas as a common cause of chronic focal seizures in children. Of 49 children undergoing resection and followed for from 1 to 14 years (mean of 5.8 years), 32 (65%) are either seizure free or have had a significant reduction in seizure frequency that has unambiguously improved their quality of life. The results are analyzed further by relating the surgical outcome to each of the pathologic entities that caused the seizures. This analysis reveals the variety of neurological conditions that commonly cause intractable focal seizure disorder in children and distinguishes those pathologic entities in which the seizure disorder is apt to respond to surgical intervention from those that will not.