Nogo-A/NgR通路参与缺血预处理对局灶性脑缺血的神经保护作用

目的研究Nogo-A/NgR通路参与缺血预处理(IPC)对局灶性脑缺血的神经保护作用。方法雄性成年SD大鼠随机分为:对照组(C)、缺血预处理组(IPC)、Tat-NEP1-40组和Tat-β-Gal组。大脑中动脉栓塞(MCAO)10min作为IPC,IPC组在IPC后72h建立MCAO致局灶性脑缺血模型。再灌注24h后,对所有动物行神经功能缺损评分(NDS),并处死大鼠取脑,应用2%TTC染色测定梗死容积和免疫组化研究Nogo-A和NgR表达变化。结果与C组比较,IPC组显著改善局灶性脑缺血再灌注后24h大鼠的NDS[2(1.5~3)和1(0~2)](P<0.01)、减少脑梗死容积[(309.65±54.61)mm3和(65.09±26.06)mm3](P<0.01),NgR拮抗剂NEP1-40可部分逆转IPC的神经保护作用(P<0.01),而其溶剂β-Gal对IPC的神经保护作用无明显影响。免疫组化显示Nogo-A和NgR阳性细胞主要位于MCAO后导致的缺血区域,缺血后24h大鼠缺血区域Nogo-A和NgR表达明显增强,IPC可抑制缺血引起的Nogo-A和NgR表达增强。结论Nogo-A/NgR通路可能参与IPC诱导的脑缺血耐受,保护脑缺血性损伤。     

可重复性小鼠局灶性脑缺血/再灌注模型的探讨

目的介绍一种标准的小鼠局灶性脑缺血/再灌注模型的制作方法,并观察不同脑缺血/再灌注时间脑梗死体积和脑水肿的变化。方法用腔内线栓法制作脑缺血/再灌注动物模型,用TTC染色法进行脑大体观察,用甲酚紫染色法观察脑切片梗死灶,用脑血流激光多普勒监测脑血流的变化,用ImageJ软件计算脑梗死体积和脑水肿。结果当线栓封闭大脑中动脉时,脑血流就会急剧下降至最低水平,拔出线栓后脑血流迅速上升至缺血前水平。脑缺血后,脑片上呈现明显的梗死灶,脑梗死体积和脑水肿的大小较恒定。脑缺血90min再灌注24h组梗死体积、脑水肿体积、脑水肿百分数及神经功能缺损程度均显著大于脑缺血30min再灌注24h组(P<0.001)。脑缺血30min/再灌注72h脑水肿非常明显(72.6±4.3)mm3,再灌注7d时脑水肿开始减退,仅为(50.9±4.1)mm3,再灌注30d时脑容积出现萎缩,脑水肿呈负值(-20.1±1.8)mm3。结论该小鼠局灶性脑缺血/再灌注模型具有重复性好、容易操作的优点。脑缺血30min就可造成不可逆性脑损害,脑水肿在再灌注72h即达到高峰。     

升压治疗局灶性脑缺血再灌注损伤的时间窗研究

目的　探讨升压治疗对局灶性脑缺血的保护作用及治疗时间窗。方法　采用大鼠局灶性脑缺血再灌注模型 ,30只大鼠随即分为 6组 :对照组、缺血即刻升压、缺血 1h升压、缺血 2h升压、缺血 3h升压、缺血 4h升压。观察血脑屏障破坏程度、脑梗死体积的情况。结果　缺血后 3h、4h升压后脑梗死体积与对照组分别为 4 0 9.96± 79.34mm3 、4 13.13± 6 8.14mm3 、4 10 .8± 87.6 9mm3 无统计学差异 (P >0 .0 5 ) ,且血脑屏障破坏程度明显大于对照组。结论　缺血 3h再灌注时 ,升压时间窗不超过 2h。     

三七三醇皂苷对脑缺血再灌注大鼠的保护作用

目的 通过对局灶性脑缺血大鼠不同再灌注时段的动态观察．探讨三七三醇皂苷(PTS)对大鼠局灶性脑缺血／再灌注动物模型的神经行为学和脑梗死体积的保护作用。方法 采用改良的线栓法制备大脑中动脉阻塞(MACO)2h、再灌注不同时间段(3h、6h、12h、24h、48h、72h、7d)的大鼠短暂局灶性脑缺血模型。动物随机分假手术组、生理盐水对照组、三七三醇皂苷(PTS)组。用Zea Longa5分制评分和TTC染色法评价神经行为学和脑梗死体积。结果 神经行为学评分除72h组有明显改善外．其余各组与生理盐水对照组比较无显著性差异。脑梗死体积除再灌注3h、6h外．其余各组与生理盐水组比较差异均有显著性意义。结论 三七三醇皂苷对大鼠局灶性脑缺血及再灌注损伤有一定的保护作用。     

3-CP对大鼠局灶性脑缺血再灌注损伤的脑保护作用

目的探讨3-CP对大鼠局灶性脑缺血再灌注损伤的脑保护作用。方法采用血管内尼龙线栓塞法建立大鼠局灶性脑缺血模型,脑缺血和再灌注通过激光多普勒监测局部脑血流来证实。所有动物均缺血1h再灌注24h,动物分为4组:实验一组(3-CP100m g/kg;n=6),实验二组(3-CP10m g/kg;n=6),实验三组(3-CP1m g/kg;n=6)和对照组(0.9%生理盐水,n=5)。3-CP和生理盐水均在再灌注开始1m in内注射入血管。脑梗塞体积用TTC染色法显示,用图象分析软件计算梗塞体积。结果实验一、二、三组和对照组脑梗塞体积分别为(44.4±16.5)m m3、(39.5±20.3)m m3、(107.0±18.3)m m3和(146.0±63.6)m m3,实验一、二组和对照组相比,相差显著(P<0.01)。结论100m g/kg3-CP和10m g/kg3-CP剂量的3-CP对大鼠局灶性脑缺血模型中再灌注损伤有神经保护作用。     

缺血后处理通过PI3K信号通路抑制脑缺血再灌注损伤

目的 研究缺血后处理(IP)对脑缺血再灌注损伤的影响及其机制.方法 采用开颅机械闭塞法建立SD大鼠局灶性脑缺血模型,通过开放/夹闭双侧颈总动脉实现IP.24只大鼠按照随机数字表法分为IP组、非IP组、LY294002+IP组、DMSO+IP组,每组6只,再灌注48 h后测脑梗死面积;其中LY294002、DMSO于建模前1 h侧脑室注入.结果 各组左侧大脑皮层均可见清晰梗死灶,符合血管分布范围.其中IP组腩梗死面积(34.02%±7.17%)明显小于非IP组(57.05%±10.05%),差异有统计学意义(P＜0.05);LY294002+IP组脑梗死面积(73.41%±2.06%)明显大于DMSO+IP组(35.76%±1.51%),差异有统计学意义(P＜0.05);DMSO+IP组与IP组脑梗死面积差异无统计学意义(P＞0.05).结论 IP可减轻局灶性脑缺血大鼠的脑缺血再灌注损伤,PI3K信号通路参与其作用机制.     

舒血宁注射液对脑缺血再灌注大鼠缺血半暗带水通道蛋白1和水通道蛋白9表达的影响

目的观察舒血宁注射液对脑缺血再灌注大鼠额顶叶皮质缺血半暗带(IP)水通道蛋白1(AQP1)和水通道蛋白9(AQP9)表达的影响。方法线栓法制作局灶性脑缺血再灌注大鼠模型(MCAO),随机分为假手术组、模型组、舒血宁注射液防治组和川芎嗪药物对照组。脑缺血2h,分别再灌注1d、3d、7d,采用免疫组化SABC法检测AQP1和AQP9蛋白表达的阳性总面积和平均吸收光密度。结果在缺血侧额顶叶皮质IP,再灌注各时间点,模型组AQP1和AQP9蛋白表达的阳性总面积和平均吸收光密度显著高于假手术组(P0.05或P0.01),舒血宁注射液和川芎嗪药物对照组再灌注1d、3d、7d,AQP1和AQP9蛋白表达的阳性总面积和(或)平均吸收光密度显著低于模型组(P0.05或P0.01)。结论舒血宁注射液能通过抑制AQP1、AQP9蛋白表达,减轻脑水肿,抗脑缺血再灌注损伤。     

腺苷预处理对大鼠脑缺血再灌注损伤后VEGF的表达

目的通过观察腺苷预处理后大鼠局灶性脑缺血再灌注区脑组织的病理结构、脑梗死面积及血管内皮生长因子(VEGF)的表达,探讨腺苷预处理诱导脑缺血耐受的可能作用机制。方法制作大鼠脑缺血再灌注损伤模型。60只SD大鼠随机分为3组:假手术组(F组)、缺血再灌注组(IR组)、腺苷预处理组(AP组),再按缺血再灌注后不同时间把各组随机分成4个亚组(每亚组5只大鼠)。通过TTC染色观察脑梗死体积,并应用免疫组化法检测各组大鼠脑组织VEGF的表达。结果 (1)TTC染色正常脑组织呈鲜红色,梗死区脑组织呈苍白色,并且随着再灌注时间的延长可见梗死区扩大,腺苷预处理组的脑梗死体积小于缺血再灌注组。(2)F组可见少量VEGF阳性表达,IR组和AP组在脑缺血再灌注后2 h开始出现VEGF阳性表达的细胞数量增多,24 h达到高峰,72 h下降,AP组在6 h、24 h VEGF阳性表达比IR组增强(P均<0.05),在72 h时AP组VEGF阳性表达较IR组减少(P<0.05)。结论腺苷预处理能够进一步增强大鼠局灶性脑缺血再灌注损伤后VEGF的表达;VEGF的表达增加可能是腺苷预处理诱导脑缺血耐受和产生神经保护作用的分子机制之一。     

缺血预处理上调TROY表达诱导大鼠局灶性脑缺血耐受

目的研究缺血预处理（IPC）对局灶性脑缺血的保护作用以及对TNFRSF expressed on the mouse embryo（TROY）表达的影响。方法33只雄性成年SD大鼠，随机分为预处理6h组（IVC-6组，11只）、预处理72h组（IPC-72组，11只）和缺血组（CI组，11只）。利用线栓法建立大脑中动脉栓塞（MCAO）致局灶性脑缺血模型。MCAO 10min作为IPC,IPC-6和IPC-72组分别在IPC后6h和72h制作短暂性局灶性脑缺血模型。再灌注24h后，对所有动物行神经功能缺损评分（NDS），并处死大鼠取脑，应用2％TTC染色测定梗死容积、TUNEL染色研究细胞凋亡情况和免疫组化观察TROY表达变化。结果与CI组比较，IPC-72组显著改善局灶性脑缺血24h后大鼠神经功能损害[两组评分分别为2（1．5-3），1（0—2）]，减少脑梗死容积[（299．33±70．98）mm^3，（69．25±47．66）mm^3]，抑制细胞凋亡和增强TROY的表达（阳性细胞数分别为42±11，87±17）（P〈0．01）。结论IPC对其后局灶性脑缺血有明显的保护作用．能诱导脑缺血耐受，可能与TROY表达上调相关。     

预防性应用阿托伐他汀对SD大鼠局部脑缺血再灌注脑组织Caspase-3表达的影响

目的 探讨预防性应用阿托伐他汀对SD大鼠局灶性脑缺血再灌注损伤是否具有脑保护作用及其可能的机制.方法 72只雄性SD大鼠,按随机化原理分成3组:假手术组(n=24)、缺血再灌注组(简称对照组n=24)、阿托伐他汀组(n=24),各组按缺血2 h再灌注2 h、6 h、24 h、36 h分为4个亚组,每组各6只.结果 各相同再灌注时间点,阿托伐他汀组与对照组比较,缺血区变性、坏死的神经元数量减少,空泡样改变减轻,组织间水肿减轻.阿托伐他汀组较对照组Caspase-3阳性表达细胞数明显减少,再灌注2 h、6 h,2组间比较差别有统计学意义(P＜0.05),再灌注24 h及36 h 2组间比较差别有显著性统计学意义(P＜0.01).结论 预防性应用阿托伐他汀能减轻SD大鼠局灶性脑缺血再灌注损伤,减轻神经细胞变性、坏死及组织水肿,使缺血周边区及海马区Caspase-3表达减少.     

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.