实验性癫痫时大鼠海马内兴奋性氨基酸受体对阿片肽含量的影响

应用免疫组织化学方法观察了青霉素致痫及海马内微量注射ＮＭＤＡ受体拮抗剂ＭＫ８０１（５－ｍｅｔｈｙ１－１０，１１－ｄｉｈｙｄｒｏ－５Ｈ－ｄｉｂｅｎｚｏ（ａ，ｄ）ｃｙｃｌｏｈｅｐｔａｎ－５，１０－ｉｍｉｎｅｍａｌｅａｔｅ）和非ＮＭＤＡ受体拮抗剂ＤＮＱＸ＊（６，７－ｄｉｎｉｔｒｏｑｕｉｎｏｘａｌｉｎｅ－２，３－ｄｉｏｎｅ）后，大鼠海马内吗啡肽Ａ１－１７和亮啡肽的含量变化，结果发现，在青霉素致痫４ｈ后，海     

兴奋性氨基酸NMDA受体激动剂N-methyl-D-aspartate对大鼠海马 CA1区神经元膜电位影响

目的应用离体大鼠海马脑片,结合细胞内记录技术,研究兴奋性氨基酸NMDA受体激动剂N-methyl-D-aspartate对大鼠海马CA1区神经元膜电位的影响。方法海马脑片随机分为单纯缺氧组(Con组,n=10)、MK801组(n=10)和NMDA25μmol/L组(NMDA组,n=8)。Con组及MK801组的海马脑片分别给予10min缺氧或在缺氧期间应用含100μmol/L MK801的aCSF;NMDA组海马脑片在膜电位稳定15min后用含有25μmol/L NMDA的aCSF灌流10min。所有海马脑片均应用正常aCSF恢复60min。记录用药前或缺氧前膜电位、缓慢去极化的速率、快速去极化时间和快速去极化的幅度及恢复60min时神经元对细胞内注入电流及经Scheffer侧支刺激的反应。结果25μmol/L NMDA可以产生与缺氧相似的膜电位变化。但MK801组神经元的快速去极化时间显著高于NMDA组和Con组(P<0.05);NMDA组的快速去极化时间则显著短于Con组(P<0.05)。MK801组神经元的缓慢去极化速率为(0.08±0.03)mv/s,显著低于NMDA组的(0.44±0.12)mv/s及Con组的(0.22±0.05)mv/s(P<0.05)。在MK801组的10例神经元中,其中9例恢复对细胞内注入电流及经Schaffer刺激的反应,产生动作电位。结论兴奋性氨基酸NMDA受体的激活可能是神经元缺氧去极化的机制之一;而其受体拮抗剂MK801则可以显著抑制缺氧期间神经元膜电位的变化,促进复氧后神经元功能的恢复。     

急性癫痫大鼠脑脊液中四种氨基酸含量的变化

本文用神经递质HPLC荧光法测定了急性致病大鼠脑脊液中四种氨基酸的含且及应用NMDA受体阻断剂MK—801后对上述指标的影响。结果：急性致痫组动物脑脊液中GIU明显增高（P＜0．05）。其它三种氨基酸变化不明显。使用MK—801后，脑脊液中Gin合且有所下降。提示：马迈内酯致痴与脑内GIu升高有关。     

兴奋性氨基酸在缺血性海马神经元损害中的作用的研究

采用大鼠全脑缺血模型,研究脑缺血再灌流海马氨基酸含量的动态变化及相应病理改变,观察NMDA(N-甲基-D-门冬氮酸)受体拮抗剂MK-801的疗效,提示兴奋性氨基酸(Glu,Asp)可能参与海马神经元损害,MK-801能有效防止海马CA_1区迟发性神经元坏死。兴奋性氨基酸受体拮抗剂的研究,将为临床缺血性中风治疗提供新的途径。     

两种钙通道拮抗剂抑制脑缺血复灌后转录因子c—Jun的表达

目的：研究两种钙离子通道：NMDA受体型和L－型电压门控钙通道（L－VGCC）在短暂全脑缺血复灌后海马c-Jun表达中的作用。方法：采用SD大鼠四动脉结扎全脑缺血模型，取缺血复灌不同时间（0,1,3,6,12,24和72h)以及对照组2D大鼠的海以，应用免疫印迹的方法来研究c-Jun的表达并观察几种钙通道拮抗剂对c-Jun表达的影响。结果：在假手术以及复灌的各个时间点均有表达，并在复灌6h达到高峰。氯胺酮（一种非竞争性NMDA受体拮抗剂）和硝苯吡啶（一种L－VGCC阻滞剂）抑制c-Jun表达的增加。而DNQX（一种AMPA／KA受体拮抗剂）则无抑制作用（数据未显示）。结论：缺血复灌后，c-Jun的表达增加了，这种增加与NMDA受体和L－VGCC这两种钙离子通道的开放有关。     

褪黑激素对青霉素所致痫样发作的预防作用

以往报道表明，褪黑激素（melatonin,MEL)对癫痫活动有作用，但结果并不一致。有实验表明MEL有抗痫,也有证据支持MEL有促痫作用。本文用海马内微量注射的方法，观察了MEL对青霉素所致痫样发作（penicillin-ionduced seizures,PIS)的影响，并对其与受体的可能作用作了探讨。发现，预先给予MEL对PIS有抑制作用，且该效应具有剂量依赖性。褪黑激素的作用可被Ⅰ型受体拮抗剂luzindole部分阻断，Ⅱ型受体拮抗剂prazosine对此无影响。结果表明，MEL对PIS有预防作用，该作用可能与MELⅠ型受体部分有关。     

低剂量伽玛刀照射对癫痫大鼠皮层及海马NMDA受体亚基表达的影响

目的观察低剂量伽玛刀照射对癫痫大鼠皮层和海马N-甲基-D-天氡氨酸(N-methyl-Daspartate,NMDA)受体亚基表达的影响。方法根据动物是否致痫及接受伽玛刀照射,将大鼠分为4组:对照组、伽玛刀组、药物致痫组、伽玛刀+药物组。腹腔连续注射戊四氮(pentylenetetrazole,PTZ)制备癫痫大鼠模型,以双侧额叶为照射靶区对大鼠进行低剂量伽玛刀照射,边缘剂量为15Gy。观察并记录各组大鼠伽玛刀照射前、后癫痫发作情况,并于伽玛刀照射后12周后留取脑组织,分别利用免疫组化及免疫蛋白印迹法对大鼠皮层及海马NMDA受体亚基NR1、NR2A和NR2B进行检测。结果对照组及伽玛刀组大鼠无痫性发作表现,与药物致痫组大鼠相比,伽玛刀+药物组大鼠经低剂量伽玛刀照射后12周,痫性发作明显减轻(P0.05)。与对照组相比,药物致痫组大鼠额叶皮层及海马CA1、CA3区NR1、NR2A和NR2B表达均明显增强(P0.05),阳性神经元数目及平均吸光度值均明显增加(P0.05);与药物致痫组比较,伽玛刀+药物组额叶皮层及海马CA1、CA3区NR1、NR2A和NR2B表达均明显降低(P0.05),阳性神经元数目及平均吸光度值明显减少(P0.05);伽玛刀组与对照组无明显差别(P0.05)。结论癫痫大鼠额叶皮层及海马NR1、NR2A及NR2B亚单位蛋白表达增强,低剂量伽玛刀照射可能引起癫痫大鼠皮层及海马NMDA受体亚基表达减少,这可能是低剂量伽玛刀抑制癫痫发作的分子机制之一。     

谷氨酸对丘脑束旁核痛兴奋神经元放电的影响

目的：观察脑室注射谷氨酸（Glu)对大鼠丘脑束旁核（PF）痛兴奋神经元（PEN）电变化的影响。方法：以电脉冲刺激右侧坐骨神经作为伤害性痛刺激，用玻璃微电极细胞外记录神经元放电的变化。结果：（1）伤害性刺激使大鼠丘脑PF的PEN诱发放电频率增加；（2）脑室注射Glu(1.5μg/10μl）加强PEN的电活动，使PEN放电频率的净增值增加，潜伏期缩短；（3）这种作用可被Glu的NMDA受体拮抗剂MK－801（0．17μg/0.5μl)所阻断。结论：Glu在中枢痛沉调制中可能起兴奋作用，而NMDA受体参与介导中枢伤害性信息的传递过程。     

皮质酮对大鼠原代海马神经细胞的毒性作用

本文探讨了皮质酮（corticosterone，CORT）对大鼠原代海马神经细胞的毒性作用及作用机制。实验结果显示，CORT加入无血清DMEM培养基可剂量依赖地损伤原代培养海马神经细胞，LD50为3．2×10－6mol／L，而原代培养的皮层神经细胞只被高浓度皮质酮（10－5mol／L和10－4mol／L）所损伤，其LD50为8.5×10－5mol／L，比前者大近20倍。原代培养的海马神经细胞补充高浓度的葡萄糖或NMDA一受体拮抗剂MK－801可显著地拮抗CORT对海马神经细胞的毒性作用。同时，CORT处理的海马神经细胞胞内ATP水平明显降低，而补充高浓度葡萄糖（25mmol／L）可逆转CORT诱导的ATP耗竭。以上结果提示，CORT可选择地损伤海马神经细胞，这一损伤作用与葡萄糖浓度相关。实验结果进一步提示，CORT对海马神经细胞的毒性作用可能与其导致的能量水平低下和兴奋性氨基酸的堆积有关．     

福尔马林致炎大鼠鞘内注射布托啡诺后脊髓背角NMDA受体的表达

研究背景与目的: 酒石酸布托啡诺是一种阿片类镇痛剂,对阿片受体具有激动/拮抗双重作用。其在临床和动物实验中的应用已有报道,但还未见鞘内应用于福尔吗林炎性痛大鼠模型的报道.另外在疼痛机制形成过程中,NMDA受体激活起着非常重要的作用。故我们假设鞘内注射酒石酸布托啡诺应用于福尔马林炎性痛大鼠时能产生明显的镇痛效果,其产生镇痛的机制可能是通过抑制NMDA受体表达来实现. 方法: 在大鼠的左后足掌面皮下注射5%福尔马林50μl致痛前30min,健康雄性SD大鼠接受生理盐水,低剂量布托啡诺（12.5μg）,高剂量布托啡诺（25μg）鞘内注射;对照组在福尔马林注射前不注射任何试剂,为了更进一步的研究,我们在设计中加入鞘内注射非选择性NMDA受体拮抗剂氯胺酮,也分别在福尔马林致痛前30min,鞘内注射低剂量（50μg）,高剂量（100μg）或低剂量（50μg）混合低剂量布托啡诺进行注射。与疼痛相关的行为学测定通过计算大鼠后爪理毛行为（后爪的离地、舔足/咬足）总计反应时间来确定,记录福尔马林诱导出注射后爪的双相理毛行为时间(在福尔马林注射后第1时相, 0-5 min; 第 2时相, 10-60 min ).所有大鼠均在注射后2h处死,用免疫组化法测定大鼠L5节段脊髓背角NMDA受体的表达。 结果：鞘内单独用布托啡诺当剂量增加到25μg时,以及鞘内低剂量布托啡诺和氯胺酮联合使用时都引起第1和2时相的后爪理毛行为的总计反应时间明显减少;其余的组别对福尔马林1和2时相都没有明显影响。鞘内单独用高剂量布托啡诺以及低剂量布托啡诺和氯胺酮联合处理都可以显著降低福尔马林致痛大鼠L5脊髓背角NMDA受体表达。 结论：本研究结果揭示鞘内用布托啡诺能够对福尔马林诱导的疼痛产生明显的镇痛作用,并具有剂量依赖性,其镇痛机制可能是通过抑制NMDA受体激活产生;不过具体NMDA受体抑制机制是否与鞘内布托啡诺激活к受体或μ受体有关还需要更进一步的研究来确定。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.