应激对大鼠海马谷氨酸、天冬氨酸和γ-氨基丁酸含量的影响

目的　探讨应激对大鼠海马谷氨酸、天冬氨酸和γ 氨基丁酸 (GABA)含量的动态影响。方法　将 72只健康雄性大鼠随机分为 5个应激暴露不同时间组和对照组 ,每组 12只。利用高效液相色谱仪 紫外检测法 ,分别于应激第 1,3,7,14和 2 8天观察应激对大鼠海马谷氨酸、天冬氨酸及GABA含量的影响。结果　应激第 1天组大鼠海马谷氨酸和天冬氨酸含量与对照组相比 ,差异无显著性 ;但GABA含量 [(2 74 7± 0 339) μmol/g]低于对照组 [(3 719± 0 5 2 8) μmol/g;P <0 0 5 ]。应激第 3,7,14和 2 8天组谷氨酸含量 [分别为 (7 818± 0 799) μmol/g ,(9 0 0 7± 0 5 2 0 ) μmol/g,(8 0 4 9± 0 733) μmol/g和 (8 12 9± 1 5 5 6 ) μmol/g]高于对照组 [(6 4 11± 0 6 38) μmol/g];天冬氨酸含量 [分别为 (2 717± 0 2 5 8)μmol/g,(2 6 96± 0 317) μmol/g,(2 82 8± 0 4 6 8) μmol/g和 (4 6 4 9± 0 6 37) μmol/g]也高于对照组 [(2 0 0 3± 0 2 71) μmol/g];均P <0 0 1。应激第 14天组和 2 8天组GABA含量 [分别为 (4 4 6 2± 0 883) μmol/g和(4 4 97± 0 85 7) μmol/g]高于对照组 (P <0 0 5～0 .0 0 1) ,应激第 3天组和 7天组的GABA含量与对照组间的差异无显著性。结论　应激第 3天开始     

Management Strategies for Refractory Localization-Related Seizures

Summary: Localization-related epilepsy, the most common type of seizure disorder, often provides major management problems. Five new antiepileptic drugs (AEDs) with different mechanisms of action have been licensed in the United Kingdom in the 1990s for adjunctive use in the management of poorly controlled partial seizures. These were, in chronologic order, vigabatrin, lamotrigine, gabapentin, topiramate, and tiagabine. Their practical deployment is explored here. Mention also is made of clobazam and acetazolamide. Combination therapy with two or even three AEDs having complementary pharmacologic effects can provide an essential contribution to the management of partial seizures. This article discusses some of the pharmacologic strategies used in treating patients with refractory localization-related epilepsy.     

Aggravation of Focal Epileptic Seizures by Antiepileptic Drugs

Summary: Aggravation of focal epileptic seizures in adults is common after the antiepileptic drug (AED) therapy is initiated. Sometimes aggravation is mimicked by clustering of the seizures. Therefore, it is always necessary to analyze the patient's history and therapy carefully before drawing any conclusions. It is likely that a paradoxical aggravation of epileptic seizures can be attributed to the given AED and is sometimes, but only rarely, due to drug interactions.     

Alcohol, Seizures, and Epilepsy

Summary: Seizures, epilepsy, and alcohol are complexly interrelated. Although it is commonly perceived that patients with epilepsy experience problems with seizure control if they use alcohol, this is not confirmed by the few experimental studies that have tested the hypothesis. The last 30 years have emphasized the role of withdrawal from alcohol as a mechanism of seizure production. However, this is but one of many potential mechanisms by which seizures and epilepsy may be related to alcohol use and abuse. The rare but clear situations in which alcohol can act as a convulsant drug need further study, and mechanisms by which the long-term neurotoxic effects of alcohol lead to chronic epilepsy also need further elucidation.     

Field-potential assay of antiepileptic drugs in the hippocampal slice

The effects of nine clinically active antiepileptic drugs and the NMDA antagonist 2-amino-7-phosphonoheptanoic acid (2-APH) were examined in three models in the in vitro hippocampal slice. In the "low Mg2+" model, removal of Mg2+ from the perfusion fluid increased excitatory neurotransmission and led to epileptogenic field potentials. In the "low Ca2+" model, decrease of Ca2+ and increase of Mg2+ and K+ in the perfusion fluid induced spontaneous "bursts" in the absence of synaptic transmission. Paired-pulse stimulation was used to estimate the strength of recurrent inhibition in the "inhibition" model. The rank order of the potency of the compounds to antagonize the second epileptogenic population spike in the low Mg2+ model was 2-APH greater than pentobarbital greater than midazolam greater than phenytoin greater than carbamazepine greater than chlordiazepoxide greater than phenobarbital = flurazepam. Ethosuximide and valproate were inactive. In the low Ca2+ model, the rank order of the potency of the drugs to antagonize spontaneous epileptogenic bursts was phenytoin greater than carbamazepine greater than midazolam greater than pentobarbital greater than chlordiazepoxide greater than flurazepam greater than phenobarbital. 2-APH, ethosuximide, and valproate were inactive. Only pentobarbital was active in the inhibition model. These experiments demonstrate the potential of in vitro tests in the hippocampus to reveal profiles of anticonvulsant activity.     

Quisqualic Acid-Induced Seizures During Development: A Behavioral and EEG Study

Summary: Quisqualic acid (QA) is an excitatory amino acid analogue that binds to the glutamate ionotropic receptor subclass AMPA (a–amino–3 hydroxy-5 methyl-4 isoxazol propionic acid) and metabotropic receptor phos-pholipase C. To study its epileptogenic properties, we administered QA through an intraventricular cannula to 23-, 41-, and 60-day-old rats with recording electrodes implanted in amygdala, hippocampus, and neocortex. The frequency power spectra of the recorded EEG was computed by fast fourier transform (FFT), and coherence between anatomic sites was computed. Seizures occurred in all animals receiving QA. The behavioral manifestations of the seizures varied as a function of age, with younger rats demonstrating rigidity and immobility followed by circling activity and intermittent forelimb clonus and 60-day-old animals exhibiting severe, wild running followed by generalized clonus. Ictal electrical discharges occurred in all animals. Neocortical ictal discharges occurred more prominently in the younger animals, and amygdala ictal discharges were more prominent in the older animals. Marked increases in spectral power occurred during the seizures in all anatomic structures and at all frequencies. Our results demonstrate that the clinical manifestations of QA seizures vary during development; results of the neurophysiologic studies suggested that neocortex may play an important role in genesis of QA seizures in immature brain.     

Excitatory amino acid antagonists protect mice against MPP+ seizures.

Administration of 1-methyl-4-phenyl-pyridinium ion (MPP+) into the lateral ventricle of mice induced clonic convulsions and lethality in a dose- and age-dependent manner. MPP+ failed to induce seizures in 4-day-old mice, and the convulsant response to MPP+ was enhanced in aged mice. The seizures triggered by MPP+ in adult mice were blocked by coadministration of L-glutamate antagonists active at kainate/AMPA receptors such as gamma-D-glutamylaminomethylsulphonate and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline. The N-methyl-D-aspartate (NMDA) antagonist 2-amino-7-phosphonoheptanoate, but not kynurenate, also protected mice against MPP+ convulsions. Similarly, the benzodiazepine midazolam and the adenosine A1 agonist 2-chloroadenosine, but not antiepileptic drugs such as phenobarbital, trimethadione, ethosuximide, or acetazolamide, showed a protective efficacy against seizures. Additionally, the excitatory amino acid antagonists as well as phenobarbital, midazolam and 2-chloroadenosine protected mice against MPP+ lethality. These data suggest that convulsant action of MPP+ and its lethality in rodents may be mediated by excitatory amino acids.     

Dicarboxylic Amino Acids Block Epileptiform Activity in Hippocampal Slice

Effects of prolonged (5-10 min) continuous perfusion of excitatory amino acids on penicillin (PEN)-evoked epileptiform activity in hippocampal slices were examined with extracellular and intracellular recordings. L-glutamate (GLU), L-aspartate (ASP), quisqualate (QUIS), and N-methyl-D,L-aspartate reversibly depressed multiple (epileptiform) population spikes elicited by PEN (1.7 mM). Intracellularly recorded, PEN-evoked paroxysmal depolarization shifts (PDS) were partially blocked by 1 mM GLU and largely eliminated by 2 mM GLU or ASP. In the presence of PEN, perfusion with both GLU and ASP induced a transient 4 to 6-mV depolarization, usually followed by spontaneous return of membrane potential to control levels. During the amino acid (AA)-induced block of epileptiform activity, there was no significant change in resting membrane potential, input resistance, or the ability to fire action potentials in response to depolarization, indicating that the decreased responsiveness is not a consequence of nonspecific pyramidal cell overdepolarization. The observed depression of epileptiform activity by continued exposure to GLU and its analogues may reflect desensitization or another regulatory mechanism to limit overexcitation.     

AMT法对接受长期药物治疗癫癎病人的倦睡评价

用一种新构建的脑电图检查方法在控制条件下探讨长期接受抗癎药治疗是否削弱了癫癎病人维持觉醒的能力.发现接受抗癎药治疗的病人平均总倦睡时间为101s,两个对照组均≤12s(P<0.001).该时间与测量方法无关.认为,长期抗癎药治疗削弱了癫癎病人维持觉醒的能力,病人服药后对倦睡的抱怨可能不精确地说明了该问题.     

GABA turnover in mouse brain: Agreement between the rate of GABA accumulation after aminooxyacetic acid and the rate of disappearance after 3-mercaptopropionic acid

Summary GABA levels of the whole mouse brain were studied afterin vivo inhibition of GABA synthesis by 3-mercaptopropionic acid (3-MPA, 100mg/kg i.p.) and of GABA degradation by aminooxyacetic acid (AOAA, 3.8–60 mg/ kg i.v.). The influence of 3-MPA on GABA levels was investigated in brains where postmortal GABA accumulation was allowed to occur and in brains where this phenomenon was avoided by very rapid dissection and homogenization of the brain in acid (within 50 sec after decapitation). The postmortal GABA increase was blocked by 86% after injection of 3-MPA 3 min before decapitation. In the group where the postmortal accumulation was avoided by very rapid homogenization of the brain in acid, GABA levels decreased by 15 % within 2 min after 3-MPA (mean turnover time=14 min). From 2 to 4 min the GABA concentration remained stable at this decreased level. GABA accumulation after AOAA was maximal after a dose of 7.5 to 15 mg/kg. i.v. Doses higher than 60mg/kg always produced convulsions. The phase of most rapid accumulation of GABA after AOAA indicates a mean turnover time of about 10 min. The first rapid phase of accumulation was followed by a slower phase. It is probable that the turnover time of whole mouse brain GABA is approximately 10–14 min. It is also concluded that AOAA in a dose of around 15 mg/kg i.v. hardly can inhibit GADin vivo in the mouse brain and that this dose, by this route of administration, could be used for studies of GABA synthesisin vivo in the mouse.     

tGLP-1 action on the isolated hypothalamo-neurohypophysial system under glutamate receptor blockade

The isolated rat hypothalamo-neurohypophysial system was used to investigate possible mechanisms of glucagon-like peptide-1 (7-36) amide (tGLP-1) effects on the vasopressin/oxytocin (AVP/OXY) release. The non-selective inhibition of synaptic transmission as brought about by excess of MgSO(4) in the incubation medium completely abolished the tGLP-1-induced AVP release and attenuated OXY secretion. The non-specific blockade of excitatory amino acid receptors with kynurenic acid (KA) completely suppressed the tGLP-1-induced AVP but not OXY release. Specific inhibition of NMDA receptors suppressed the tGLP-1-evoked AVP release without affecting tGLP-1-induced OXY secretion. Selective blockade of non-NMDA receptors did not affect either tGLP-1-induced AVP or OXY release. It is concluded that tGLP-1 can influence the function of AVP neurons indirectly, most probably via the glutamatergic system through NMDA receptors. On the other hand, tGLP-1-evoked activation of OXY neurons, at least in part, seems to be a result of direct tGLP-1 activation of these neurons.     

An analogue of Joro spider toxin selectively suppresses hippocampal epileptic discharges induced by quisqualate

The anticonvulsant effect of 1-naphthylacetyl spermine, an analogue of Joro spider toxin (JSTX), was studied against seizures induced by quisqualate (QUIS), a non-NMDA agonist, as assessed electrophysiologically and behaviorally in freely moving rats. Electrodes were implanted into right dorsal hippocampus and an injection cannula ofr drugs into right ventricle. The pretreatment with JSTX analogue significantly inhibited both of QUIS-induced hippocampal discharges (80-11%) and generalized tonic clonic seizures (100-33%) in a dose-dependent manner, whereas JSTX had no effect no seizures induced by quinolinate, a NMDA agonist. The paper provides the first direct evidence that the JSTX analogue exerts a potent and selective suppression of hippocampal epileptic discharges mediated by non-N-methyl-d-asparta (non-NMDA) receptors.     

阿魏酸钠对谷氨酸盐诱导的成年小鼠神经毒性的保护作用

目的 研究阿魏酸钠(SF)对谷氨酸单钠(MSG)诱导的成年小鼠神经兴奋性毒性的保护作用.方法 60只昆明小鼠采用数字随机表法分为对照组、SF组、MSG组、MSG+SF组[根据SF剂量不同,又分为20、40、80mg/(kg·d)三个亚组],每组各10只.MSG组小鼠灌胃MSG[2.0g/(kg·d)],MSG+SF组MSG[2.0g/(kg·d)]灌胃的同时腹腔注射SF[20、40、80mg/(kg·d)],SF组腹腔注射SF[40mg/(kg·d)],每日1次,连续给药10d;对照组灌胃和腹腔注射同量生理盐水.通过小鼠的行为学实验和脑海马组织病理检查,分析MSG所引起的功能和形态学上的变化以及SF的保护作用.结果 末次给药后第6天MSG组Y-迷宫正确反应次数比例(13.80/20)显著少于对照组(16.42/20),差异有统计学意义(P<0.01);MSG[2.0g/(kg·d)]+SF[(40mg/(kg·d)]组Y-迷宫正确反应次数比例(16.30/20)与对照组差异无统计学意义(P>0.05).MSG组小鼠海马细胞水肿、神经元变性坏死和组织增生;MSG[2.0g/(kg·d)]+SF[(40mg/(kg·d)]组海马未发现明显的组织病理学改变. 结论SF能部分抵消MSG诱导的成年小鼠行为障碍和脑海马病理组织损伤;SF对MSG诱导的成年小鼠神经兴奋性毒性存在保护作用.     

Effects of some excitatory amino acid antagonists on imipenem-induced seizures in DBA/2 mice

The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABA_A agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (±)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((±)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) . 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 ? Msc ? (−)-2-amino-7-phosphonic acid (AP7) > γ-D-glutamylaminomethylsulphonate (γ-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABA_A agonist, was able to protect against seizures induced by Imi.     

儿童癫痫及抗癫痫治疗对血脂水平影响的研究

对１１４例儿童癫痫患者的血脂水平进行监测。结果发现癫痫本身对血脂水平无影响，抗癫痫药物治疗后总胆固醇和甘油三产高，且随治疗时间的延长差异更为明显，高密度脂蛋白无变化。丙戊酸钠对血脂无影响，而苯舀英钠，苯巴比舀，卡马西平可使ＴＣ，ＴＧ明显升高。     

Seizures in HIV-seropositive individuals: NIMHANS experience and review

Seizures are not uncommon in patients with human immunodeficiency virus (HIV) infection, and with the upsurge in HIV infection this may be an important cause for acute symptomatic seizures. Seizures may rarely be the presenting manifestation of HIV infection. Opportunistic infections such as toxoplasmosis, tuberculosis, progressive multifocal leucoencephalopathy (PML), cryptococcal meningitis and polymicrobial infections, metabolic and electrolyte disturbances, and drugs are common causes of new-onset seizures in HIV-seropositive individuals. In the absence of any cause, primary HIV infection may be considered responsible for seizures. Because seizures tend to recur in and because they are a poor prognostic indicator in HIV infection, treatment with antiepileptic drugs (AEDs) is the norm. The treatment of HIV-infected individuals with seizures comprises of the administration of AEDs, specific treatment of the underlying conditions, and antiretroviral drugs. Clinicians must consider both therapy-compromising drug–drug and drug–disease interactions while choosing appropriate AEDs. The ideal AED in this setting is one that does not affect viral replication, have limited protein binding, and have no effects on the hepatic cytochrome P450 enzyme system. The risks for AED-induced allergic skin rash appears to be high in HIV-seropositive individuals.     

儿童癫痫及抗癫痫治疗对甲状腺功能影响的前瞻性研究

采用放射免疫分析法动态观察４０例儿童癫痫的甲状腺功能，结果发现癫痫本身对甲状腺功能无影响，而诱导肝酶类抗癫痫药如苯妥英钠、卡马西平、苯巴比妥可使Ｔ４降低。且随治疗时间的增长降低更明显，Ｔ３、ＴＳＨ无明显改变。丙戊酸钠对甲状腺功能无影响。提示对癫痫患儿要常规监测甲状腺功能，对同时有甲状腺疾病病史及其他可引起甲状腺功能改变的情况者，丙戊酸钠优于诱导肝酶类的抗癫痫药。     

Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy

High-dose treatment with pilocarpine hydrochloride, a cholinergic muscarinic agonist, induces seizures in rodents following systemic or intracerebral administration. Pilocarpine seizures are characterized by a sequential development of behavioral patterns and electrographic activity. Hypoactivity, tremor, scratching, head bobbing, and myoclonic movements of the limbs progress to recurrent myoclonic convulsions with rearing, salivation, and falling, and status epilepticus. The sustained convulsions induced by pilocarpine are followed by widespread damage to the forebrain. The amygdala, thalamus, olfactory cortex, hippocampus, neocortex, and substantia nigra are the most sensitive regions to epilepsy-related damage following convulsions produced by pilocarpine. Spontaneous seizures are observed in the long-term period following the administration of convulsant doses of pilocarpine. Developmental studies show age-dependent differences in the response of rats to pilocarpine. Seizures are first noted in 7-12 day-old rats, and the adult pattern of behavioral and electroencephalographic sequelae of pilocarpine is seen in 15-21-day-old rats. During the third week of life the rats show an increased susceptibility to the convulsant action of pilocarpine relative to older and younger animals. The developmental progress of the convulsive response to pilocarpine does not correlate with evolution of the brain damage. The adult pattern of the damage is seen after a delay of 1-2 weeks in comparison with the evolution of seizures and status epilepticus. The susceptibility to seizures induced by pilocarpine increases in rats aged over 4 months. The basal ganglia curtail the generation and spread of seizures induced by pilocarpine. The caudate putamen, the substantia nigra, and the entopeduncular nucleus govern the propagation of pilocarpine-induced seizures. The antiepileptic drugs diazepam, clonazepam, phenobarbital, valproate, and trimethadione protect against pilocarpine-induced convulsions, while diphenylhydantoin and carbamazepine are ineffective. Ethosuximide and acetazolamide increase the susceptibility to convulsant action of pilocarpine. Lithium, morphine, and aminophylline also increase the susceptibility of rats to pilocarpine seizures. The pilocarpine seizure model may be of value in designing new therapeutic approaches to epilepsy.     

Risk of Age-Related Fractures in Patients with Unprovoked Seizures

The incidence of age-related fractures was determined in a cohort of 467 Rochester, Minnesota residents with unprovoked seizures. The 30 initial hip fractures observed were significantly more than the 13.19 expected [standardized morbidity ratio (SMR) = 2.3; 95% confidence interval (CI) 1.5-3.3]. The overall incidence of distal forearm (Colles) fractures was not significantly increased (SMR = 1.6; 95% CI 0.9-2.5), based on 17 cases. Hip fracture incidence was increased during the first 10 years after seizure diagnosis but was not related to anti-epileptic drug (AED) use. In contrast, the increase in Colles' fracture incidence was associated with duration of therapy, as the SMR for greater than or equal to 10 years of AED use was 2.4 (95% CI 1.0-5.0). The incidence of vertebral fractures was slightly higher among treated patients but was not associated with duration of AED use. Thus, there was no consistent pattern to support the contention that fracture incidence is greatly increased by long-term AED use.