左旋多巴治疗对实验性帕金森病大鼠黑质纹状体TNF—a表达的影响

目的　研究左旋多巴 (L - dopa)治疗对实验性帕金森病 (PD)大鼠黑质纹状体肿瘤坏死因子(TNF-α)表达的影响。方法　黑质定位注射 6 -羟多巴胺 (6 - OHDA )制备偏侧 PD大鼠模型 ,经 5 0～ 10 0 mg/ kg体重 L - dopa灌胃治疗 4周后 ,检测双侧额叶皮质、黑质和纹状体区域 TNF-α的表达。结果　 6 - OHDA损毁侧黑质和纹状体 TNF-α含量和阳性细胞面密度分别显著高于健侧 (均 P<0 .0 5 )。损毁侧与健侧 TNF-α含量的比率随 L - dopa治疗用量的增加而增高 ,且均显著高于对照组 (P<0 .0 5 )。结论　 L - dopa治疗进一步加剧了PD大鼠黑质纹状体区域 TNF-α的高表达。     

左旋多巴诱发异动症大鼠皮质纹状体突触超微结构与功能的变化

目的　探讨左旋多巴诱发异动症 (levodopainduceddyskinesias ,LID)大鼠皮质纹状体突触结构和功能的变化。方法　 6 羟多巴胺 (6 OHDA)立体定位注射制备偏侧帕金森病 (Parkinsondisease,PD)大鼠模型 ,复方左旋多巴 (L dopa)甲酯腹腔注射治疗 4周 (2 0mg·kg-1·d-1,每天 2次 )诱发LID大鼠模型。采用免疫组化及透射电镜方法对大鼠皮质纹状体突触界面的结构进行定量分析 ,并观察单次地佐环平 (MK 80 1,0 1mg/kg)治疗后突触前谷氨酸 (Glu)释放量的变化。结果　透射电镜证实皮质Glu能纤维与纹状体神经元的树突棘构成不对称突触 ,与PD大鼠比较 ,LID大鼠Glu能非对称性突触中穿孔性突触进一步增加 (P <0 0 1) ,且突触间隙变窄 ,突触后致密物质 (post synapticdensity ,PSD)厚度增加 (P <0 0 5 )。同时伴有突触前Glu释放量的增多 ,但可被N 甲基 D 门冬氨酸 (NMDA)受体拮抗剂MK 80 1所抑制。结论　慢性L dopa治疗使皮质纹状体突触功能进一步活化 ,其中涉及突触后形态和功能的改变及突触前活性的增强 ,这些突触可塑性变化与LID的发生密切相关     

反义FosB和反义CREB基因抑制左旋多巴诱发异动症大鼠前强啡肽原基因的表达

目的探讨纹状体内转录调控因子FosB基因和环-磷酸腺苷应答元件结合蛋白(CREB)基因对左旋多巴诱发异动症(LID)大鼠前强啡肽原(PDyn)基因表达的影响。方法6-羟基多巴(6-OHDA)立体定位注射及慢性左旋多巴(L-dopa)治疗诱发LID大鼠模型,所有大鼠共分为对照组(n=10)、对照+反义FosB组(n=12)、对照+正义FosB组(n=13)、对照+反义CREB组(n=11)、对照+正义CREB组(n=13)、LID组(n=10)、LID+反义FosB组(n=9)、LID+正义FosB组(n=7)、LID+反义CREB组(n=8)、LID+正义CREB组(n=8)。对照组与LID组分别注射PBS,其余各组大鼠纹状体内分别注射相应反义、正义FosB和CREB。后4组大鼠进行异常不自主运动(AIM)评分,并采用原位杂交方法观察大鼠纹状体内PDyn mRNA的变化。结果反义FosB治疗前后LID大鼠AIM评分分别为40.1±9.2、12.5±5.4,差异有统计学意义(P<0.01)。LID+反义FosB组损毁侧纹状体PDyn mRNA水平(吸光度,0.2415±0.0220)较LID+正义FosB组损毁侧(吸光度,0.4105±0.0386)显著降低(P<0.01)。对照+CREB组大鼠损毁侧纹状体PDyn mRNA水平(吸光度,0.1775±0.0246)较对照组(吸光度,0.2403±0.0323)明显降低(P<0.01)。反义CREB治疗前后LID大鼠AIM评分分别为40.5±10.0、43.2±11.8,差异无统计学意义(P>0.05)。LID+反义CREB组损毁侧纹状体PDyn mRNA水平(吸光度,0.2415±0.0220)与LID+正义CREB组(吸光度,0.4087±0.0440)之间差异无统计学意义(P>0.05)。结论在LID大鼠中,FosB蛋白取代了CREB调控PDyn mRNA的表达,是发生LID的关键因素之一。     

左旋多巴治疗对实验性帕金森病大鼠黑质纹状体TNF-α表达的影响

目的 研究左旋多巴(L-dopa)治疗对实验性帕金森病(PD)大鼠黑质纹状体肿瘤坏死因子(TNF-α)表达的影响.方法 黑质定位注射6-羟多巴胺(6-OHDA)制备偏侧PD大鼠模型,经50～100 mg/kg体重L-dopa灌胃治疗4周后,检测双侧额叶皮质、黑质和纹状体区域TNF-α的表达.结果 6-OHDA损毁侧黑质和纹状体TNF-α含量和阳性细胞面密度分别显著高于健侧(均P<0.05).损毁侧与健侧TNF-α含量的比率随L-dopa治疗用量的增加而增高,且均显著高于对照组(P<0.05).结论 L-dopa治疗进一步加剧了PD大鼠黑质纹状体区域TNF-α的高表达.     

多巴胺D1和谷氨酸NMDA受体参与调控异动症大鼠纹状体△FosB蛋白的表达

目的研究多巴胺D1和D2受体以及谷氨酸NMDA受体对△FosB蛋白表达水平的影响,由此探讨它们在左旋多巴诱导的异动症(Levodopa-induced Dyskinesia,LID)发病机制中的作用。方法对单侧黑质纹状体6-羟多巴胺(6-OHDA)损毁致帕金森病(PD)大鼠给予左旋多巴治疗28d制作LID模型,将大鼠分为7组:正常对照组、PD组、LID组、SCH23390治疗组、MK-801治疗组、raclopride治疗组和非LID组,分别观察各组行为学改变并进行异常不自主运动(abnormal involuntary movement,AI M)评分,用免疫组化和免疫印迹方法测定各组△FosB蛋白表达水平。结果多巴胺D1受体阻断剂SCH23390和谷氨酸NMDA受体阻断剂MK-801明显减轻LID大鼠行为学异常,而多巴胺D2受体阻断剂raclopride对异常不自主运动无明显影响;LID大鼠损毁侧纹状体△FosB蛋白表达较PD大鼠和非LID大鼠明显增加;与LID大鼠相比,MK-801和SCH23390均使△FosB蛋白表达显著下降,而raclopride没有这种效应;各组大鼠健侧纹状体△FosB蛋白表达水平没有显著差异。结论多巴胺D1受体和谷氨酸NMDA受体均通过参与调控纹状体△FosB蛋白的表达而影响大鼠LID的发生。     

左旋多巴诱发异动症大鼠模型纹状体神经元可塑性的研究

目的 研究左旋多巴诱发异动症(LID)大鼠模型纹状体区FosB和特异性神经肽基因表达的变化，探讨LID时纹状体神经元的可塑性。方法 分别用免疫组织化学方法和逆转录聚合酶链反应技术(RT-PCR)检测大鼠纹状体区FosB和前脑啡肽原(PPE)及前强啡肽原(PDyn)基因的表达情况。用辣根过氧化物酶(HRP)逆行示踪与免疫组织化学相结合的双重反应技术观测FosB的细胞分布状况。结果 帕金森病(PD)大鼠较正常大鼠损毁侧纹状体PPE mRNA表达明显增多而PDyn mRNA表达减少。LID大鼠较PD大鼠PPE mRNA无明显增多，但PDyn mRNA显著性增多。LID大鼠损毁侧纹状体区FosB阳性神经元明显增多，并且主要分布于纹状体黑质神经元内。结论 纹状体黑质神经元内即早基因FosB及其下游靶基因强啡肽的表达异常与大鼠LID的发生有关，表明LID的发生与直接通路的活动异常密切相关。     

地佐环平对左旋多巴引起帕金森病大鼠行为和基底节Fos表达的影响

左旋多巴诱导的异动症 (levodopa induceddyskinesia,LID)是长期左旋多巴治疗帕金森病 (Parkinson’sdisease,PD)的不良反应。皮质纹状体谷氨酸神经元活性增强可能参与其发生机制。鉴于近年来对长期左旋多巴治疗诱导的PD大鼠异常不自主运动 (AIM )与人类LID相似性的认识 ,我们研究了谷氨酸受体拮抗剂地佐环平 (MK 80 1)对左旋多巴诱导的AIM大鼠行为学和基底节区神经元活性的影响。材料和方法 :健康SD雄性大鼠 (2 0 0～ 2 5 0 g) ,采用 6 羟基多巴胺 (6 OHDA)立体定向注射术制备PD大鼠模型。每天 2次给予PD大鼠左旋多巴 (10mg/…     

左旋多巴诱导帕金森病异动症与纹状体DARPP-32磷酸化的关系

目的观察帕金森病(PD)异动症(LID)大鼠模型纹状体区多巴胺和环磷腺苷调节的磷酸化蛋白-32(DARPP-32)蛋白Thr75位点磷酸化表达数量及表达位点的改变。方法给予PD大鼠模型左旋多巴治疗21d,评估大鼠行为学变化;采用免疫荧光和Western blot检测大鼠纹状体区DARPP-32蛋白Thr75位点磷酸化表达数量和表达部位的改变情况。结果 PD大鼠长期使用左旋多巴出现类似于人类LID行为学表现。免疫荧光结果显示PD组和LID组大鼠损伤侧DARPP-32(Thr75)的表达多位于强啡肽阳性神经元。Western blot结果显示PD组大鼠损伤侧DARPP-32(Thr75)表达为(159.90±7.22)%,与假手术组比较升高(P<0.05);LID组大鼠损伤侧纹状体DARPP-32(Thr75)的表达为(52.60±4.45)%,与假手术组和PD组比较降低(P<0.05)。结论纹状体黑质投射神经元内DARPP-32蛋白Thr75位点磷酸化表达的改变可能参与了LID的发病。     

PD大鼠健侧纹状体多巴胺能系统的功能性改变

应用快速周期伏安法 (FCV)在体监测电刺激内侧前脑束 (MFB)诱发的正常和帕金森病 (PD)大鼠健侧及损毁侧纹状体 (Str)内多巴胺 (DA)的释放 ,并结合高效液相色谱电化学检测法 (HPLC ECD)测定Str内DA及其代谢产物的含量 ,从在体和离体水平分别对PD大鼠健侧及损毁侧Str区DA的释放及代谢进行观察及评价。实验采用自身对照 ,先用FCV监测DA的释放 ,后行HPLC ECD离体测定Str内DA及其代谢产物的含量。结果表明 :(1)在PD大鼠损毁侧 ,用FCV技术几乎不能监测到DA的释放 ,而在健侧Str区监测到的DA释放量远大于正常对照 (P <0 .0 1) ;(2 )高效液相色谱测定结果为 :PD大鼠健侧Str区DA ,DOPAC和HVA的含量均在正常范围内 ,但DA的更新率与正常大鼠相比升高 (P <0 .0 5 )。损毁侧Str内DA及其代谢产物的含量均降低 (以DA的减少最明显 ) ,而DA的更新速度加快 (P <0 .0 1)。结果提示 :6 OHDA单侧损毁的PD大鼠损毁侧DA能系统的功能性改变对健侧有影响。     

左旋多巴对健康老年大鼠脑内多巴胺转运体的影响

目的　探讨长期应用左旋多巴 (L dopa)对健康老年大鼠脑内多巴胺转运体 (DAT)的影响。方法　将健康老年大鼠随机分为A、B、C 3组 ,分别每日给予口服大剂量L dopa(15 0mg/kg)、小剂量L dopa(5 0mg/kg)和生理盐水共 4个月。停药 2 4h后 ,经尾静脉注射 99mTc TRODAT 10 2ml(80 0 μGi) ,3h后处死。剥离纹状体、大脑皮质、小脑、脑干 ,称湿重 ,测定放射性计数 ,计算脑组织ID值。结果　纹状体放射活性ID值A组、B组分别为 0 .76 4± 0 .12 9和 0 .92 8± 0 .14 5 ,明显低于C组 (1.5 6 2± 0 .2 89) (P <0 0 0 1,P <0 0 5 ) ,其他部位差异无显著性。结论　长期应用L dopa可以导致纹状体部位DAT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.     

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.     

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.     

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.