Recent advances in drug therapy for epilepsy.

Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug''s bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects.     

Melatonin ameliorates sodium valproate-induced hepatotoxicity in rats

Molecular Biology Reports - Valproic acid (VPA) is a anticonvulsant and mood-stabilizing agent used to treat epilepsy in patients of all ages. However, it can cause hepatotoxicity with increased...     

Glial cells as primary therapeutic targets for epilepsy

Neurons have been the natural focus of discussion for most of the history of research on seizures and epilepsy. Simply stated, epilepsy is a disease of sporadic, progressive disruption of neuronal activity. Thus causes and therapies for epilepsy have been naturally aimed at the obvious manifestation of disease: neuronal dysfunction. However, over the last two decades a new view is beginning to emerge that is defining the dependence of neuronal function and seizure susceptibility on glia. This view changes the definition of epilepsy as a disease of neurons to a disease of a heterogeneous neuronal-glial network. This new glial focus is suggesting new opportunities to treat the nearly 1/3 of individuals who do not respond to traditional antiepileptic drug (AEDs) therapies as well as suggesting ways to reduce the many unwanted side effects of AEDs.     

浅析肠道菌群干预治疗癫痫的潜在应用前景

肠道菌群是存在于人体内的庞大而复杂的微生物群落,菌群的变化会影响大脑的生理、行为和认知功能,而大脑可以通过免疫、内分泌和神经通路等途径调节神经生理行为,与很多神经和精神疾病(如癫痫、脱髓鞘疾病、阿尔茨海默症、自闭症等)的发生发展有关。近年来诸多证据表明自身免疫机制在癫痫进展中发挥重要作用,肠道菌群可通过调节免疫反应来影响疾病的进展。本文从肠道菌群与大脑间关系的认知、相互间功能影响及与癫痫的关系等方面,探讨通过肠道菌群干预治疗癫痫的机制与潜在应用前景,希望为菌群干预治疗与预防一些神经及精神疾病提供参考。     

Activation of AMPK by the Putative Dietary Restriction Mimetic Metformin Is Insufficient to Extend Lifespan in Drosophila

The biguanide drug, metformin, commonly used to treat type-2 diabetes, has been shown to extend lifespan and reduce fecundity in C. elegans through a dietary restriction-like mechanism via the AMP-activated protein kinase (AMPK) and the AMPK-activating kinase, LKB1. We have investigated whether the longevity-promoting effects of metformin are evolutionarily conserved using the fruit fly, Drosophila melanogaster. We show here that while feeding metformin to adult Drosophila resulted in a robust activation of AMPK and reduced lipid stores, it did not increase lifespan in either male or female flies. In fact, we found that when administered at high concentrations, metformin is toxic to flies. Furthermore, no decreases in female fecundity were observed except at the most toxic dose. Analysis of intestinal physiology after metformin treatment suggests that these deleterious effects may result from disruptions to intestinal fluid homeostasis. Thus, metformin appears to have evolutionarily conserved effects on metabolism but not on fecundity or lifespan.     

Laboratory animal models of temporal lobe epilepsy

Temporal lobe epilepsy is a common human disease that is difficult to treat. The pathogenesis of temporal lobe epilepsy, which holds many unresolved questions, and opportunities for creating more effective treatments and preventative strategies are reviewed herein. Laboratory animal models are essential to meet these challenges. How models are created, how they compare with each other and with the disease in human patients, and how they advance our understanding of temporal lobe epilepsy are described.     

Theoretical investigation of the neuronal Na+ channel SCN1A: abnormal gating and epilepsy

Epilepsy is a paroxysmal neurological disorder resulting from abnormal cellular excitability and is a common cause of disability. Recently, some forms of idiopathic epilepsy have been causally related to genetic mutations in neuronal ion channels. To understand disease mechanisms, it is crucial to understand how a gene defect can disrupt channel gating, which in turn can affect complex cellular dynamic processes. We develop a theoretical Markovian model of the neuronal Na+ channel NaV1.1 to explore and explain gating mechanisms underlying cellular excitability and physiological and pathophysiological mechanisms of abnormal neuronal excitability in the context of epilepsy. Genetic epilepsy has been shown to result from both mutations that give rise to a gain of channel function and from those that reduce the Na+ current. These data may suggest that abnormal excitation can result from both hyperexcitability and hypoexcitability, the mechanisms of which are presumably distinct, and as yet elusive. Revelation of the molecular origins will allow for translation into targeted pharmacological interventions that must be developed to treat syndromes resulting from divergent mechanisms. This work represents a first step in developing a comprehensive theoretical model to investigate the molecular mechanisms underlying runaway excitation that cause epilepsy.     

术中皮质脑电图监测癫痫病灶切除13例分析

目的:探讨继发性癫痫术中运用皮质脑电图监测切除癫痫病灶的疗效。方法:对13例继发性癫痫患者术前经多次常规脑电图、24h动态脑电图检查定位并联合CT、MRI等检查结果,确定癫痫病灶的准确位置。在皮质脑电图精确定位监测下手术切除致痫灶。结果:13例癫痫患者均通过皮质脑电图监测,准确定位,切除致痫灶,切除病灶后的棘波、尖波,棘、尖慢复合波减少或完全消失。结论:利用皮质脑电图监测手术切除痫灶是治疗继发性癫痫最有效的方法之一。     

Medical Aspects of Violence

Physicians see violence in beaten wives, battered children, rage reactions, murder, and suicide. They should recognize that it may be a symptom of disease if it is unprovoked or bizarre, or is associated with impaired consciousness, confusion or irrationality. Violence in episodic trance-like states suggests limbic disease (temporal lobe lesions, psychomotor epilepsy, or “dyscontrol syndrome”); in association with personality change, dementia, or psychosis, it indicates cortical disease (structural, toxic, or idiopathic).     

The Effect of Time of Administration of Phenytoin on its Serum Levels and Pharmacodynamic Parameters in Patients of Generalised Tonic Clonic Seizures

The role of the time of administration of phenytoin on its serum levels and pharmacodynamic parameters was studied in two comparable groups of patients of grand mal_epilepsy stabilized on serum phenytoin therapy. In these patients, phenytoin was advised to be taken as a single daily dose either at 08.00 (Group M) or 20.00 (Group E) every day. A serum phenytoin level profile over 24 hours was obtained and all patients were clinically followed up for six months. Maximum serum concentration (C-max) of phenytoin was achieved significantly faster (p < 0.001) in patients of Group E. The total number of serum samples having toxic concentrations and also the incidence and severity of toxic effects of phenytoin was less in Group E. The study suggests that bedtime administration of phenytoin in patients of grand mal–epilepsy may lead to faster absorption of the drug and less side effects as compared with drug administration in the morning.     

Contributions of astrocytes to epileptogenesis following status epilepticus: Opportunities for preventive therapy?

Status epilepticus (SE) is a life threatening condition that often precedes the development of epilepsy. Traditional treatments for epilepsy have been focused on targeting neuronal mechanisms contributing to hyperexcitability, however, approximately 30% of patients with epilepsy do not respond to existing neurocentric pharmacotherapies. A growing body of evidence has demonstrated that profound changes in the morphology and function of astrocytes accompany SE and persist in epilepsy. Astrocytes are increasingly recognized for their diverse roles in modulating neuronal activity, and understanding the changes in astrocytes following SE could provide important clues about the mechanisms underlying seizure generation and termination. By understanding the contributions of astrocytes to the network changes underlying epileptogenesis and the development of epilepsy, we will gain a greater appreciation of the contributions of astrocytes to dynamic circuit changes, which will enable us to develop more successful therapies to prevent and treat epilepsy. This review summarizes changes in astrocytes following SE in animal models and human temporal lobe epilepsy and addresses the functional consequences of those changes that may provide clues to the process of epileptogenesis.     

Synthesis and in vitro characterization of platinum(II) anticancer coordinates using FTIR spectroscopy and NCI COMPARE: A fast method for new compound discovery

Platinum-based drugs have been used for several decades to treat various cancers successfully. Cisplatin is the original compound in this class; it cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types but exhibits toxic side effects; in addition, tumors often develop resistance. An original in vitro approach is proposed to determine whether platinum-based research compounds are good candidates for further study by comparing them to marketed drugs using FTIR spectroscopy and the COMPARE analysis from the NCI. Both methods can produce fingerprints and highlight differences between the compounds, classifying the candidates and revealing promising derivatives.     

Epilepsy in the elderly and depression

Epilepsy is one of the most common neurological problems affecting approximately 1% of the world's population with higher incidence among elderly individuals. Although depression is a common comorbid condition in patients with epilepsy, there is a paucity of information regarding depression in geriatric patients with epilepsy. This study analysed a group of 83 patients affected by different epilepsy phenotypes accompanied by mental disorders, especially depression. Antiepileptic and antipsychotic drug treatment has been evaluated, particularly a positive effect of the new antiepileptics (monotherapy and polytherapy) both on the reduction of seizures and mental disorders.     

Models and detection of spontaneous recurrent seizures in laboratory rodents

Epilepsy,characterized by spontaneous recurrent seizures (SRS),is a serious and common neurological disorder afflicting an estimated 1％ of the population worldwide.Animal experiments,especially those utilizing small laboratory rodents,remain essential to understanding the fundamental mechanisms underlying epilepsy and to prevent,diagnose,and treat this disease.While much attention has been focused on epileptogenesis in animal models of epilepsy,there is little discussion on SRS,the hallmark of epilepsy.This is in part due to the technical difficulties of rigorous SRS detection.In this review,we comprehensively summarize both genetic and acquired models of SRS and discuss the methodology used to monitor and detect SRS in mice and rats.     

Tetanus toxin as a tool for studying epilepsy

The use of tetanus toxin, injected into the hippocampus of the rat, to produce an "animal model" of chronic limbic epilepsy is described. This model has yielded information complementary to that derived from other animal models and has several important advantages: while it involves spontaneous seizures, it occurs without gross damage to the brain ; it is eventually reversible in terms of fits and the overall reappearance of the EEG. It can therefore be used to look both at the effects of ongoing epilepsy and also at the long-term changes in brain function induced by previous epilepsy. Evidence is presented that the toxin probably remains localised at the site of injection. The information which has so far been obtained with this model on the relation between epilepsy and abnormal behaviour is summarised. In particular, it appears that the epilepsy produces long-term deficits in the animals' ability to learn and remember of a sort which suggest that an enduring malfunction has been induced in the hippocampus. The significance of the findings for clinical research and for future investigation of the nature of epilepsy are described. It is emphasised that the neurotoxins may be usefully exploited not only for investigating the molecular basis of neuronal mechanisms but also for inducing long-lasting plastic changes in integrated brain function.     

Characterization of PTZ-induced seizure susceptibility in a down syndrome mouse model that overexpresses CSTB

Down syndrome (DS) is a complex genetic syndrome characterized by intellectual disability, dysmorphism and variable additional physiological traits. Current research progress has begun to decipher the neural mechanisms underlying cognitive impairment, leading to new therapeutic perspectives. Pentylenetetrazol (PTZ) has recently been found to have positive effects on learning and memory capacities of a DS mouse model and is foreseen to treat DS patients. But PTZ is also known to be a convulsant drug at higher dose and DS persons are more prone to epileptic seizures than the general population. This raises concerns over what long-term effects of treatment might be in the DS population. The cause of increased propensity for epilepsy in the DS population and which Hsa21 gene(s) are implicated remain unknown. Among Hsa21 candidate genes in epilepsy, CSTB, coding for the cystein protease inhibitor cystatin B, is involved in progressive myoclonus epilepsy and ataxia in both mice and human. Thus we aim to evaluate the effect of an increase in Cstb gene dosage on spontaneous epileptic activity and susceptibility to PTZ-induced seizure. To this end we generated a new mouse model trisomic for Cstb by homologous recombination. We verified that increasing copy number of Cstb from Trisomy (Ts) to Tetrasomy (Tt) was driving overexpression of the gene in the brain, we checked transgenic animals for presence of locomotor activity and electroencephalogram (EEG) abnormalities characteristic of myoclonic epilepsy and we tested if those animals were prone to PTZ-induced seizure. Overall, the results of the analysis shows that an increase in Cstb does not induce any spontaneous epileptic activity and neither increase or decrease the propensity of Ts and Tt mice to myoclonic seizures suggesting that Ctsb dosage should not interfere with PTZ-treatment.     

昆虫抗菌肽在医药上的应用

柞蚕抗菌肽有广谱杀菌作用,能抑制乙型肝料病毒DNA复制,又能选择杀伤肿瘤细胞。属于一类具有明确化学结构及杀菌功能的成份,又有新作用靶位及不同于一般抗菌素的作用机制,对动物安全、无毒、无副作用。在医药上已制成“肾肝宁”胶囊治疗肾炎及肝炎。以免疫血淋巴干冻粉制成柞蚕素胶胶囊治疗乙型肝炎,已取得临床试验批文。现将进一步把抗菌肽纯化为单体,作为治疗耐药性细菌感染的消化道炎症的新药,以克服常用抗生素的毒、副作用和易引起病菌抗药性的弱点。抗菌肽开发成一类新药有广阔的开发前景。     

A Hamilton-Jacobi-Bellman approach for termination of seizure-like bursting

We use Hamilton-Jacobi-Bellman methods to find minimum-time and energy-optimal control strategies to terminate seizure-like bursting behavior in a conductance-based neural model. Averaging is used to eliminate fast variables from the model, and a target set is defined through bifurcation analysis of the slow variables of the model. This method is illustrated for a single neuron model and for a network model to illustrate its efficacy in terminating bursting once it begins. This work represents a numerical proof-of-concept that a new class of control strategies can be employed to mitigate bursting, and could ultimately be adapted to treat medically intractible epilepsy in patient-specific models.     

熊胆在朝医临床中的应用

朝医药是朝鲜民族在长期生活经验中总结出的抵抗病邪的智慧结晶,其理论核心是四象医学,在治疗上,倡导“药乃局限于人”的药性观。熊胆是熊科动物黑熊或棕熊的胆汁,其性味苦、寒,具有清热解毒,明目,止痉的功效。在朝医药中,熊胆属于太阴人药,具有活血化瘀,发汗等作用。通过对熊胆在临床上的应用以及有关其基础的研究,发现在药物的应用方面朝医药与中医药之间存在着有些差异,这种差异给药物的基础研究以及临床应用开辟了更多新思路,可使各民族医药之间取长补短。     

熊胆在朝医临床中的应用

朝医药是朝鲜民族在长期生活经验中总结出的抵抗病邪的智慧结晶,其理论核心是四象医学,在治疗上,倡导"药乃局限于人"的药性观。熊胆是熊科动物黑熊或棕熊的胆汁,其性味苦、寒,具有清热解毒,明目,止痉的功效。在朝医药中,熊胆属于太阴人药,具有活血化瘀,发汗等作用。通过对熊胆在临床上的应用以及有关其基础的研究,发现在药物的应用方面朝医药与中医药之间存在着有些差异,这种差异给药物的基础研究以及临床应用开辟了更多新思路,可使各民族医药之间取长补短。