p38丝裂原活化蛋白激酶与缺血性脑损伤

丝裂原活化蛋白激酶(mitogen activated protein kinase．MAPK)超家族广泛分布于细胞浆内。是一族含有丝氨酸／苏氨酸残基的蛋白激酶，是将细胞外刺激信号传递到细胞核．引起细胞生物学反应的重要信号传导系统。目前MAPK超家族在哺乳动物中至少发现4种亚家族，分别为细胞外信号调节激酶(extracelluar signal regulated protein kinase，     

p38丝裂原活化蛋白激酶通路及其相关神经系统方面的研究进展

生物的信号转导(signal transduction)指细胞感知各种胞外刺激后,通过细胞内信号分子的逐级传递作用,诱导细胞各种生理生化反应所需基因表达开始的过程。丝裂原活化蛋白激酶(mitogen activated proteinkinase,MAPK)级联反应途径是细胞内的主要信息传递系统,可将细胞外信息传递至细胞核中,从而介导细胞产生各种反应,在细胞的增殖、分化和凋亡过程中发挥重要作用,并在所有真核生物细胞中表达,属于丝氨酸/苏氨酸蛋白激酶。研究表明MAPK信号转导途径在中枢神经系统广泛表达,各种细胞外刺激信号,包括神经递质、神经营养因子、生长因子等均可通过这一通路影响突触传递、神经元的重塑、形态分化和生存等,从而参与神经系统多种疾病的病理过程。一、MAPK信号转导途径概述MAPK级联反应包括3级成员:MAPK、丝裂原活化蛋白激酶激酶(mitogen activated protein kinase kinase,MAPKK)和丝裂原活化蛋白激酶激酶激酶(mitogen activated protein kinase kinasekinase,MAPKKK),它们都是具有11个保守亚结构区域的蛋白激...     

p38促分裂原活化蛋白激酶在神经病理性疼痛中的作用

促分裂原活化蛋白激酶(MAPKs)家族是细胞内重要的信号传导系统,并在神经可塑性以及炎症反应方面发挥重要作用。MAPKs家族包括3个家庭成员:细胞外信号调节激酶、c-Jun氨基末端激酶和p38MAPK。p38 MAPK信号通路是MAPKs家族信号通路的枢纽,诱导多种与神经性病理疼痛相关的细胞内反应。p38 MAPK可以作为神经元和胶质细胞中研究疼痛的靶标,为疼痛性疾病的治疗提供一个潜在治疗方案。     

C-jun氨基末端激酶与缺血性脑损伤

丝裂原活化蛋白激酶（mitogen-activated protein kinases,MAPKs）信号通路之一c-Jun氨基末端激酶（c-Jun amino-terminal kinase,JNK）是广泛存在神经细胞中的一条信号转导途径,由一组级联活化的丝/苏氨酸蛋白激酶组成,对于细胞凋亡有重要调控作用.文章对JNK在脑缺血性损伤中的激活作用作简要介绍.     

MAPK/ERK激酶-ERK信号通路参与外源性bFGF对缺氧-复氧损伤后星形胶质细胞内Egr-1结合活性的调节(英文)

目的静脉注射碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)可以明显降低实验性脑缺血大鼠的脑梗死面积,但该作用的分子机制尚不清楚。本文旨在研究外源性bFGF 作用的信号转导通路。方法缺氧-复氧损伤星形胶质细胞。Western blot检测外源性bFGF作用后丝裂原活化蛋白激酶/细胞外信号调节激酶激酶(mitogen-activated protein kinase/extracellular signal-regulated kinase kinase,MEK)-细胞外信号调节激酶(extracellular signal-regulated kinase, ERK) 信号通路活化。电泳变动迁移率分析实验检测外源性bFGF 作用后核转录因子早期生长反应因子-1(early growth respons factor 1, Egr-1)的结合活性变化。结果外源性bFGF可以保护胞外信号调节激酶MEK-ERK信号通路蛋白不被氧自由基降解。MEK-ERK信号通路在外源性bFGF作用后活化。这一信号通路进一步使Egr-1结合活性升高。结论外源性bFGF可能通过激活ERK信号通路,促进内源性转录因子Egr-1的结合活性升高,进而促进内源性bFGF的表达。     

ERK5激酶及其与神经系统发生发展及疾病的关系

丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）是丝氨酸／苏氨酸蛋白激酶的一个家族，可将细胞外刺激传递至细胞内，对生长因子和不同形式的压力作出应答，是真核细胞中主要的激酶传导通路。MAPKs调节细胞许多功能，包括细胞增殖、分化、新陈代谢和凋亡。     

MAPK/ERK激酶-ERK信号通路参与外源性bFGF对缺氧-复氧损伤后星形胶质细胞内Egr-1结合活性的调节

目的 静脉注射碱性成纤维细胞生长因子（basic fibroblast growth factor,bFGF）可以明显降低实验性脑缺血大鼠的脑梗死面积,但该作用的分子机制尚不清楚。本文旨在研究外源性bFGF 作用的信号转导通路。方法缺氧-复氧损伤星形胶质细胞。Western blot检测外源性bFGF作用后丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（mitogen-activated protein kinase/extracellular signal-regulated kinase kinase,MEK）-细胞外信号调节激酶（extracellular signal-regulated kinase, ERK） 信号通路活化。电泳变动迁移率分析实验检测外源性bFGF 作用后核转录因子早期生长反应因子-1（early growth respons factor 1, Egr-1）的结合活性变化。结果外源性bFGF可以保护胞外信号调节激酶MEK-ERK信号通路蛋白不被氧自由基降解。MEK-ERK信号通路在外源性bFGF作用后活化。这一信号通路进一步使Egr-1结合活性升高。结论外源性bFGF可能通过激活ERK信号通路,促进内源性转录因子Egr-1的结合活性升高,进而促进内源性bFGF的表达。     

P38MAPK信号转导通路与血管细胞增殖及缺血再灌注的关系

丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是广泛表达的丝氨酸/酪氨酸激酶,在真核生物细胞多种信号转导通路中起重要的作用,受多种因素的调控,作用底物多种多样。P38信号通路是MAPK通路中相当重要的一个分支,在炎症、细胞应激、凋亡、细胞周期和生长等多种生理、病理过程中起着重要作用。     

NRG-1亚型及相关信号通路在周围神经疾病中的研究

<正>神经调节蛋白-1(neuregulin-1,NRG-1)是一组含有表皮样生长因子(epidermal growth factor,EGF)结构域的蛋白,其与酪氨酸激酶受体Erb B2(receptor tyrosine-protein kinase erb B-2,Erb B2)结合后,激动下游的Ras蛋白/丝裂原活化蛋白激酶(ras protein-mitogen-activated protein kinase,RasMAPK)和磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol3-phosphate kinase-protein kinase B,PI3K-AKT)信号通路,从     

MAP激酶在脑血管痉挛中的作用研究进展

促分裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是细胞内重要的信号系统,通过这一系统将细胞外刺激传递到细胞核,介导细胞反应。目前在哺乳动物的细胞内至少发现了5个不同类型的MAPK家族:MAPKerk1/2、MAPKp38、MAPKjnk、MAPKerk3/4和MAPKerk5。它们通过对底物的     

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.     

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.     

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.     

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.     

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.     

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.