ARHGAP12在小鼠戊四氮癫痫模型中的表达

目的观察Rho GTP酶激活蛋白12(Rho GTPase-activating protein 12,ARHGAP12)在戊四氮(pentylenetetrazol,PTZ)致癫小鼠模型中的表达情况。方法 25只C57BL/6小鼠随机分为癫痫组和对照组。分别应用Westernblot和免疫组织化学染色检测ARHGAP12的表达情况;应用免疫荧光染色对ARHGAP12进行定位。结果ARHGAP12定位于神经元的细胞膜;在癫痫模型中,ARHGAP12的表达水平较对照组明显增高(*P <0. 05,**P <0. 01)。结论 ARHGAP12定位于海马神经元的细胞膜;在小鼠PTZ癫痫模型中,ARHGAP12高表达,提示其可能参与癫痫的形成。     

A neural model theory leading to kindling effect of epilepsy

The dynamics of neural nets constructed of discrete populations of formal neurons were investigated, beginning with the study of single probabilistic nets which were called netlets. The dynamics of these netlets was extended to include steady or slowly varying excitatory or inhibitory inputs. Results obtained with this approach showed simple hysteresis phenomena. However, by considering that the neural connections can be set up by means of chemical markers carried by the individual neurons the dynamics of such systems exhibits not only simple hysteresis but also multiple phenomena. Such hysteresis loops may be considered to represent the basis for short-term memory. The later study of probabilistic neural nets with chemical markers was generalized by considering the intrinsic noise of the system, caused by the spontaneous release of synaptic transmitter substance. On the basis of these studies of noisy neural nets we proposed a model for epileptic phenomena and a theory leading to kindling effect of epilepsy.     

A review of vitamin K, epilepsy and pregnancy

Based on a case history of fetal haemorrhage due to maternal antiepileptic treatment and a review of 40 previously described similar cases, it is recommended that epileptic mothers receive vitamin K tablets throughout the month before delivery and intravenously during labour. It is further recommended that phytomenadione should be administered intravenously to the infant immediately after birth. Cord blood specimens should be submitted for immediate clotting studies and if diminished vitamin K-dependent factors are found, fresh frozen plasma should be given at a dose of 20 ml/kg over a period of 1-2 h. Alternatively, the drug treatment of women with epilepsy during pregnancy could be changed from liver enzyme inducing drugs to clonazepam, which is a benzodiazepine without liver enzyme-inducing properties. Further, no malformations have been reported in connection with this drug.     

Prevention of epilepsy by taurine treatments in mice experimental model

An experimental model based on kainic acid (KA) injections replicates many phenomenological features of human temporal lobe epilepsy, the most common type of epilepsy in adults. Taurine, 2‐aminoethanesulfonic acid, present in high concentrations in many invertebrate and vertebrate systems, is believed to serve several important biological functions. In addition, it is believed to have a neuroprotective role against several diseases. In the present study, an experimental mouse model based on taurine pretreatment prior to KA administration has been improved to study whether taurine has a neuroprotective effect against KA‐induced behavior and cell damage. Under different treatments tested, taurine's most neuroprotective effects were observed with intraperitoneal taurine injection (150 mg/kg dosage) 12 hr before KA administration. Thus, a reduction in or total absence of seizures, together with a reduction in or even disappearance of cellular and molecular KA‐derived effects, was detected in mice pretreated with taurine compared with those treated only with KA. Moreover, the use of tritiated taurine revealed taurine entry into the brain, suggesting possible changes in intracellular:extracellular taurine ratios and the triggering of pathways related to neuroprotective effects. © 2008 Wiley‐Liss, Inc.     

Serum levels of beta-carotene, alpha-carotene, and vitamin A in patients with amyotrophic lateral sclerosis

To elucidate whether serum alpha and beta-carotene and retinol levels are related with the risk for amyotrophic lateral sclerosis (ALS), we compared serum levels of alpha-carotene, beta-carotene, and retinol (vitamin A), measured by HPLC, in 40 patients with amyotrophic lateral sclerosis (ALS) and 87 matched controls using an isocratic high performance liquid chromatography technique. The mean serum alpha and beta-carotene, and retinol levels did not differ significantly between the 2 study groups. These values were not influenced by the clinical form (spinal vs bulbar) of ALS, and they did not correlate with age, age at onset, and duration of the disease. These results suggest that serum alpha and beta-carotene and retinol concentrations are unrelated with the risk for ALS.     

Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice

Psychiatric disorders frequently occur in patients with epilepsy, but the relationship between epilepsy and psychopathology is poorly understood. Frequent comorbidities in epilepsy patients comprise major depression, anxiety disorders, psychosis and cognitive dysfunction. Animal models of epilepsy, such as the pilocarpine model of acquired epilepsy, are useful to study the relationship between epilepsy and behavioral dysfunctions. However, despite the advantages of mice in studying the genetic underpinning of behavioral alterations in epilepsy, mice have only rarely been used to characterize behavioral correlates of epilepsy. This prompted us to study the behavioral and cognitive alterations developing in NMRI mice in the pilocarpine model of epilepsy, using an anxiety test battery as well as tests for depression, drug-induced psychosis, spatial memory, and motor functions. In order to ensure the occurrence of status epilepticus (SE) and decrease mortality, individual dosing of pilocarpine was performed by ramping up the dose until onset of SE. This protocol was used for studying the consequences of SE, i.e. hippocampal damage, incidence of epilepsy with spontaneous recurrent seizures, and behavioral alterations. SE was terminated by diazepam after either 60, 90 or 120 min. All mice that survived SE developed epilepsy, but the severity of hippocampal damage varied depending on SE length. In all anxiety tests, except the elevated plus maze test, epileptic mice exhibited significant increases of anxiety-related behavior. Surprisingly, a decrease in depression-like behavior was observed in the forced swimming and tail suspension tests. Furthermore, epileptic mice were less sensitive than controls to most of the behavioral effects induced by MK-801 (dizocilpine). Learning and memory were impaired in epileptic mice irrespective of SE duration. Thus, the pilocarpine-treated mice seem to reflect several of the behavioral and cognitive disturbances that are associated with epilepsy in humans. This makes these animals an ideal model to study the neurobiological mechanisms underlying the association between epilepsy and psychopathology.     

Anti-epileptogenic Clinical Trial Designs in Epilepsy: Issues and Options

Although trials with anti-seizure drugs have not shown anti-epileptogenic or disease-modifying activity in humans, new compounds are on the horizon that may require novel trial designs. We briefly discuss the unique challenges and the available options to identify innovative clinical trial designs that differentiate novel anti-epileptogenic and disease-modifying compounds, preferably early in phase II, from current anti-seizure drugs. The most important challenges of clinical testing of agents for epilepsy prevention include having sufficient preclinical evidence for a suitable agent to proceed with a human trial of an anti-epileptogenic drug, and to demonstrate the feasibility of doing such a trial. Major challenges in trial design to assess agents for disease modification include the choice of suitable study parameters, the identification of a high-risk study population, the type of control, the time and duration of treatment, and a feasible follow-up period.     

A potential model of pediatric posttraumatic epilepsy

Preclinical models of pediatric posttraumatic epilepsy (PTE) are lacking. We hypothesized that traumatic brain injury (TBI), induced by controlled cortical impact, in immature rats would cause electroencephalographic (EEG) epileptiform activity and behavioral seizures. TBI or sham craniotomy was performed on postnatal day 17. Using video-EEG monitoring 4–11 months post-TBI, most TBI rats (87.5%) showed EEG spiking and one had spontaneous, recurrent seizures. Controls showed neither EEG spikes nor electrographic/behavioral seizures. Late seizures were rare after TBI, but EEG spiking was common and may represent a surrogate for PTE.     

Targeting the endocannabinoid system in the amygdala kindling model of temporal lobe epilepsy in mice

The endocannabinoid system can be considered as a putative target to affect ictogenesis as well as the generation of a hyperexcitable epileptic network. Therefore, we evaluated the effect of a CB1 receptor agonist (WIN55.212-2) and of an inhibitor of the enzymatic degradation of the endocannabinoid anandamide (fatty acid hydrolase inhibitor URB597) in the amygdala kindling model of temporal lobe epilepsy. Only minor effects on seizure thresholds and seizure parameters without a clear dose-dependency were observed in fully kindled mice. When evaluating the impact on kindling acquisition, WIN55.212-2 significantly delayed the progression of seizure severity. In contrast, URB597 did not affect the development of seizures in the kindling paradigm. Analysis of cell proliferation and neurogenesis during the kindling process revealed that URB597 significantly reduced the number of newborn neurons. These data give first evidence that CB1-receptor activation might render a disease-modifying approach. Future studies are necessary that further analyze the role of CB1 receptors and to confirm the efficacy of CB1-receptor agonists in other models of chronic epilepsy.     

雷帕霉素对未成年癫痫模型大鼠的毒性作用

目的利用戊四氮(pentylenetetrazol,PTZ)慢性点燃Sprague Dawley大鼠(SD大鼠)模型观察在点燃初期腹腔注射雷帕霉素(rapamycin,RAPA)能否抑制癫痫发生以及雷帕霉素在治疗中的安全性。方法将6~8周龄SD雄性大鼠随机分为雷帕霉素干预组PTZ+RAPA及其对照组PTZ+NS(normal saline)及NS组,观察1周(w)、2周(w)、4周(w)、6周(w)共4个时间点,每亚组12只,观察实验动物体质量的变化、死亡率及癫痫发作情况。结果各组实验大鼠的死亡率:PTZ+RAPA组为22.9%,PTZ+NS组为10.4%,NS组为0%。PTZ+RAPA组与PTZ+NS组各个相对应的时间点(1 w,2 w,4 w,6 w)体质量差均有统计学差异(P0.001)。6周时PTZ+RAPA组的点燃率为66.7%,PTZ+NS组的点燃率为58.3%,二者无统计学差异(P0.05)。PTZ+RAPA组与PTZ+NS组相对应时间点(1 w,2 w,4 w,6 w)发作分值的两两比较差异无统计学意义(P0.05)。结论雷帕霉素未能减少或抑制未成年大鼠的癫痫发作,但能明显降低未成年SD大鼠的体质量,可能有一定的毒副作用。     

A predictive risk model for medical intractability in epilepsy

ObjectiveThis study aimed to investigate early predictors (6 months after diagnosis) of medical intractability in epilepsy.MethodsAll children < 12 years of age having two or more unprovoked seizures 24 h apart at Xinhua Hospital between 1992 and 2006 were included. Medical intractability was defined as failure, due to lack of seizure control, of more than 2 antiepileptic drugs at maximum tolerated doses, with an average of more than 1 seizure per month for 24 months and no more than 3 consecutive months of seizure freedom during this interval. Univariate and multivariate logistic regression models were performed to determine the risk factors for developing medical intractability. Receiver operating characteristic curve was applied to fit the best compounded predictive model.ResultsA total of 649 patients were identified, out of which 119 (18%) met the study definition of intractable epilepsy at 2 years after diagnosis, and the rate of intractable epilepsy in patients with idiopathic syndromes was 12%. Multivariate logistic regression analysis revealed that neurodevelopmental delay, symptomatic etiology, partial seizures, and more than 10 seizures before diagnosis were significant and independent risk factors for intractable epilepsy. The best model to predict medical intractability in epilepsy comprised neurological physical abnormality, age at onset of epilepsy under 1 year, more than 10 seizures before diagnosis, and partial epilepsy, and the area under receiver operating characteristic curve was 0.7797. This model also fitted best in patients with idiopathic syndromes.ConclusionA predictive model of medically intractable epilepsy composed of only four characteristics is established. This model is comparatively accurate and simple to apply clinically.     

Penicillin-induced epilepsy model in rats: dose-dependant effect on hippocampal volume and neuron number

This study was designed to evaluate the penicillin-induced epilepsy model in terms of dose-response relationship of penicillin used to induce epilepsy seizure on hippocampal neuron number and hippocampal volume in Sprague-Dawley rats. Seizures were induced with 300, 500, 1500 and 2000IU of penicillin-G injected intracortically in rats divided in four experimental groups, respectively. Control group was injected intracortically with saline. Animals were decapitated on day 7 of treatment and brains were removed. The total neuron number of pyramidal cell layer from rat hippocampus was estimated using the optical fractionator method. The volume of same hippocampal areas was estimated using the Cavalieri method. Dose-dependent decrease in hippocampal neuron number was observed in three experimental groups (300, 500 and 1500IU of penicillin-G), and the effects were statistically significant when compared to the control group (P<0.009). Dose-dependent decrease in hippocampal volume, on the other hand, was observed in all three of these groups; however, the difference compared to the control group was only statistically significant in 1500IU of penicillin-G injected group (P<0.009). At the dose of 2000IU penicillin-G, all animals died due to status seizures. These results suggest that the appropriate dose of penicillin has to be selected for a given experimental epilepsy study in order to demonstrate the relevant epileptic seizure and its effects. Intracortical 1500IU penicillin-induced epilepsy model may be a good choice to practice studies that investigate neuroprotective mechanisms of the anti-epileptic drugs.     

A model for internalized stigma in children and adolescents with epilepsy

ObjectivePerceptions of stigma in children and adolescents with epilepsy are associated with higher rates of mental health problems. The purpose of this study was to test relationships in a model that identified variables most strongly associated with perceptions of stigma in children and adolescents with epilepsy. Our ultimate goal is to develop a theoretical foundation for future intervention research by identifying variables associated with perceptions of stigma that are potentially amenable to psychosocial interventions.MethodsParticipants were 173 children and adolescents with epilepsy who were between 9 and 14 years of age. Data were collected in telephone interviews. Stigma was measured using a self-report scale. Data were analyzed using structural equation modeling.ResultsGreater need for information and support, more fear and worry related to having epilepsy, greater seizure severity, and younger age were significantly associated with greater perceptions of stigma. Female gender, greater need for information and support, having at least one seizure in the past year, and lower self-efficacy for seizure management were significantly associated with more fear and worry related to having epilepsy.ConclusionsFindings suggest that perceptions of stigma are associated with two variables that are amenable to psychosocial interventions: fear and worry about having epilepsy and need for information and support. Future research should test the efficacy of interventions that reduce fear and worry, provide information about epilepsy, and reduce need for support.     

癫痫患者及慢性癫痫大鼠脑组织生长抑素的测定及意义

为揭示生长抑素（ＳＯＭ）与癫痫发生的关系。采用放射免疫法检测了癫痫患者脑脊液及戊四氮诱发的慢性癫痫大鼠脑组织ＳＯＭ放射免疫活性。结果显示：癫痫患者脑脊液中ＳＯＭ含量显著高于对照组；慢性癫痫大鼠顶叶皮层、海马内ＳＯＭ含量亦显著高于对照组。提示：ＳＯＭ与癫痫发作有关。     

Brain mitochondrial metabolic dysfunction and glutamate level reduction in the pilocarpine model of temporal lobe epilepsy in mice

Although certain metabolic characteristics such as interictal glucose hypometabolism are well established for temporal lobe epilepsy (TLE), its pathogenesis still remains unclear. Here, we performed a comprehensive study of brain metabolism in a mouse model of TLE, induced by pilocarpine–status epilepticus (SE). To investigate glucose metabolism, we injected mice 3.5–4 weeks after SE with [1,2-¹³C]glucose before microwave fixation of the head. Using ¹H and ¹³C nuclear magnetic resonance spectroscopy, gas chromatography—mass spectrometry and high-pressure liquid chromatography, we quantified metabolites and ¹³C labeling in extracts of cortex and hippocampal formation (HF). Hippocampal levels of glutamate, glutathione and alanine were decreased in pilocarpine–SE mice compared with controls. Moreover, the contents of N-acetyl aspartate, succinate and reduced nicotinamide adenine dinucleotide (phosphate) NAD(P)H were decreased in HF indicating impairment of mitochondrial function. In addition, the reduction in ¹³C enrichment of hippocampal citrate and malate suggests decreased tricarboxylic acid (TCA) cycle turnover in this region. In cortex, we found reduced ¹³C labeling of glutamate, glutamine and aspartate via the pyruvate carboxylation and pyruvate dehydrogenation pathways, suggesting slower turnover of these amino acids and/or the TCA cycle. In conclusion, mitochondrial metabolic dysfunction and altered amino-acid metabolism is found in both cortex and HF in this epilepsy model.     

Antiepileptic effect of gap-junction blockers in a rat model of refractory focal cortical epilepsy

PURPOSE: Epilepsy is the most common serious neurologic disease, and current treatments are ineffective for or=1 h before drug infusion and for >or=3 h afterward. No ill effects were observed. RESULTS: An immediate and marked reduction in percentage of seizure time was seen in rats receiving carbenoxolone (baseline, 69.4%+/- 7.0% (SEM); maximum effect, 9.3%+/- 3.5%, p 相似文献