p38MAPK对耐苯妥英钠和卡马西平癫痫模型大鼠电生理和行为的影响

目的 观察p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38MAPK)信号通路抑制剂SB202190对耐苯妥英钠和卡马西平大鼠电生理指标和行为学的影响.方法 建立慢性杏仁核点燃癫痫模型,筛选出耐药大鼠,通过侧脑室注射SB202190,对照组注射生理盐水.观察其对各组大鼠后放电阈值(after discharge threshold,ADT)和行为学的影响.结果 相对于对照组,耐药组大鼠在给予SB202190后,ADT明显高于对照组(P＜0.05);Racine行为分级明显下降(P＜0.05).结论 阻断p38MAPK信号通路可以协助AEDs改善耐药大鼠的电生理活动,降低点燃后发作分级,提示p38MAPK信号通路参与了难治性癫痫的耐药.     

XIAP对耐苯妥英纳和卡马西平癫痫模型大鼠电生理和行为的影响

鼠在给予XIAP反义寡核苷酸后,ADT明显高于对照组(P<0.05);ADD时程明显缩短,Racine行为分级明显下降(P<0.05).结论 下调XIAP表达可以协助AEDs改善耐药大鼠的电生理活动,降低点燃后发作分级,提示XIAP参与了难治性癫痫的耐药.     

P-糖蛋白对卡马西平和苯妥英钠通过大鼠血脑屏障影响的研究

目的观察P糖蛋白(Pglycoprotein,PGP)拮抗剂维拉帕米对卡马西平和苯妥英钠通过大鼠血脑屏障的影响,探讨PGP在难治性癫癎多药耐药机制中的作用。方法在健康大鼠大脑皮质内安置微透析探针,腹腔注射卡马西平(20mg/kg)和苯妥英钠(50mg/kg),在给药后不同时间点收集透析液,并用高效液相技术检测其中的药物浓度,通过微透析探针局部给予维拉帕米,观察后者能否提高大鼠皮质脑细胞外液中抗癫药物的浓度。结果维拉帕米升高了脑细胞外液中卡马西平[60min:(1.74±0.28)μg/ml,90min:(1.87±0.31)μg/ml]和苯妥英钠[30min:(1.08±0.30)μg/ml;60min:(1.54±0.22)μg/ml;150min:(0.91±0.19)μg/ml]的药物浓度,前者在给药后60～90min显著增高(P<0.05),后者在给药后30～150min显著增高(P<0.05)。结论PGP限制卡马西平和苯妥英钠顺利通过血脑屏障,降低脑皮质细胞外液抗癫癎药物浓度,难治性癫时PGP表达增加可能是引起患者对抗癫癎药物产生多药耐药的原因。     

耐苯巴比妥钠难治性癫痫大鼠模型的研究

目的 探索耐苯巴比妥钠(PB)杏仁核点燃大鼠模型的建立并评价其可靠性.方法 采用苯巴比妥钠对37只杏仁核成功点燃大鼠进行筛选.根据后放电阈值(after-discharge thershold,ADT)的变化判断点燃大鼠对PB的敏感及耐药情况,并测定大鼠不同1)(域脑组织P-糖蛋白(P-gtycoprotein,PGP)的表达.结果 :(1)耐药组大鼠运用PB前、后AIYT无显著性变化(P>0.05);有效组大鼠运用PB前、后ADT有显著性变化(P<0.05).(2)耐药组大鼠脑组织的PGP表达较有效组显著增强,具有统计学差异(P<0.05,0.01).结论 用PB对杏仁核点燃大鼠进行耐药筛选以制备难治性癫痫大鼠动物模型进行难治性癫痫领域的研究是可行的.     

多药转运蛋白对匹罗卡品癫(癎)大鼠模型脑内拉莫三嗪浓度的影响

目的 观察多药转运蛋白[P-糖蛋白(P-glycoprotein,PGP)和多药耐药相关蛋白(multi-drug resistance associated protein,MRP)]对匹罗卡品慢性癫(癎)大鼠模型海马内拉莫三嗪浓度的影响,探讨PGP和MRP在难治性癫(癎)多药耐药机制中的作用.方法 建立匹罗卡品慢性癫(癎)动物模型,在模型大鼠海马内安置微透析探针,腹腔注射拉莫三嗪(10mg/kg)后于不同时间点收集透析液,并用高效液相色谱检测其中的药物浓度.通过微透析探针局部分别给予PGP拮抗剂维拉帕米和MRP拮抗剂丙磺舒,观察维拉帕米和丙磺舒对模型鼠海马内神经元细胞外液拉莫三嗪浓度的影响.结果 维拉帕米明显升高了癫(癎)大鼠海马细胞外液拉莫三嗪的药物浓度,在给药后60、90、120、150 min(0.65±0.11、0.84±0.09、0.70±0.09和0.58±0.08)与模型组(0.41±0.10、0.50±0.04、0.39±0.09和0.30±0.06)比较差异有统计学意义(F=5.01、8.61、10.23、7.89,P<0.05),丙磺舒也提高了海马内拉莫三嗪的浓度,给药后90、120、150 min(0.75±0.09、0.58±0.10和0.49±0.07)与模型组比较差异有统计学意义(F=6.58、4.56、4.75,P<0.05).结论 PGP和MRP均能够限制拉莫三嗪通过癫(癎)大鼠血脑屏障,从而降低了海马内拉莫三嗪的药物浓度,上述机制可能参与了难治性癫(癎)耐药的发生.     

低频电刺激丘脑底核对癫(癎)大鼠海马谷氨酸和γ-氨基丁酸表达的影响

目的 探讨低频电刺激(LFS)丘脑底核对癫(癎)大鼠海马谷氨酸(Glu)及γ-氨基丁酸(GABA)表达的影响.方法 用30只大鼠制备杏仁核电刺激点燃模型,同时在丘脑底核埋置刺激电极;制模成功的大鼠随机分为LFS组及对照组;两组大鼠每日点燃1次,共10 d;LFS组大鼠每次点燃前予以LFS丘脑底核.观察10 d后两组大鼠癫(癎)发作程度和持续时间,应用免疫组化法测定大鼠海马Glu、GABA阳性细胞数及灰度值.结果 与对照组比较,LFS组癫(癎)发作的Racine评分明显降低,癫(癎)发作持续时间明显缩短;海马GABA阳性细胞数明显增多、灰度值降低;Glu阳性细胞数明显减少,灰度值明显增加(均P＜0.05＝.结论 LFS丘脑底核能有效抑制大鼠杏仁核点燃发作,其作用机制可能是改变了脑内Glu、GABA的表达.     

甲氧明对青霉素致癎大鼠发作行为与皮层脑电图的影响

目的探讨α1受体激动剂甲氧明对青霉素致癎大鼠发作行为学与皮层脑电图的影响。方法建立大鼠青霉素点燃模型,分别腹腔注射或海马注射甲氧明,按照改良racine分级标准,观察对大鼠发作行为学的影响以及皮层脑电图的变化。结果甲氧明腹腔注射预处理组达到I级的潜伏期(32.5±12.4)min比生理盐水组(15.2±8.1)min明显延长;甲氧明组racine分级均在Ⅱ级或Ⅱ级以下,生理盐水组全部达到Ⅳ级(P<0.01)。海马注射甲氧明预处理组脑电图癎性放电潜伏期(24′6″±5′53’″)较空白组(8′41″±1′13″)和生理盐水组(6′31″±1′43″)明显延长;生理盐水组与未预先处理组无明显统计学差异。与腹腔注射生理盐水相比,腹腔注射甲氧明对脑电图癎性放电改变没有统计学差异(P>0.05),海马注射甲氧明组与海马注射生理盐水组有明显统计学差异(P<0.01),海马注射甲氧明可以减少性放电。结论甲氧明延缓青霉素诱导癫癎的发展进程并降低癎性发作强度;甲氧明海马注射抑制青霉素癫癎模型皮层脑电图性放电程度;中枢α1肾上腺素受体参与青霉素诱导癫癎的抑制作用。     

MK-801对耐苯妥英钠和卡马西平癫(癎)大鼠模型脑表达P-糖蛋白的影响

癫(癎)是神经科仅次于脑血管意外的常见疾病,其中大约有30%的患者对多种抗癫(癎)药物表现耐药,癫(癎)发作得不到有效控制,被称之为难治性癫(癎).难治性癫(癎)患者对药物产生耐药的机制还不明确.研究表明癫(癎)病灶内高度表达P-糖蛋白(P-glycoprotein,PGP)[1],PGP是一种多药转运蛋白,能够分解ATP获能从而逆浓度梯度将抗癫(癎)药物转运出脑组织,减少了癫(癎)病灶内的药物浓度,降低了药物的疗效,上述机制可能参与了难治性癫(癎)患者对多种抗癫(癎)药物产生耐药.     

MK-801对耐苯妥英钠和卡马西平癫(癎)大鼠模型脑表达P-糖蛋白的影响

癫(癎)是神经科仅次于脑血管意外的常见疾病,其中大约有30%的患者对多种抗癫(癎)药物表现耐药,癫(癎)发作得不到有效控制,被称之为难治性癫(癎).难治性癫(癎)患者对药物产生耐药的机制还不明确.研究表明癫(癎)病灶内高度表达P-糖蛋白(P-glycoprotein,PGP)[1],PGP是一种多药转运蛋白,能够分解ATP获能从而逆浓度梯度将抗癫(癎)药物转运出脑组织,减少了癫(癎)病灶内的药物浓度,降低了药物的疗效,上述机制可能参与了难治性癫(癎)患者对多种抗癫(癎)药物产生耐药.     

MK-801对耐苯妥英钠和卡马西平癫(癎)大鼠模型脑表达P-糖蛋白的影响

癫(癎)是神经科仅次于脑血管意外的常见疾病,其中大约有30%的患者对多种抗癫(癎)药物表现耐药,癫(癎)发作得不到有效控制,被称之为难治性癫(癎).难治性癫(癎)患者对药物产生耐药的机制还不明确.研究表明癫(癎)病灶内高度表达P-糖蛋白(P-glycoprotein,PGP)[1],PGP是一种多药转运蛋白,能够分解ATP获能从而逆浓度梯度将抗癫(癎)药物转运出脑组织,减少了癫(癎)病灶内的药物浓度,降低了药物的疗效,上述机制可能参与了难治性癫(癎)患者对多种抗癫(癎)药物产生耐药.     

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.