全麻药对抑制性配体门控离子通道的作用研究进展

全麻药的作用机理一直是麻醉学领域的研究热点之一。以往人们根据挥发性麻醉药特殊的理化特性，认为全麻药主要作用在膜脂质，提出了膜的疏水区学说、容积膨胀学说，试图揭示其脂溶性与麻醉强度的关系（Meyer-Overto．1法则），但在实验中有许多违背此法则的现象，膜脂质学说受到越来越多的挑战。近年来随着分子生物学技术、膜通道技术的快速发展，全麻机制研究取得较大的进展，1994年Franks提出膜蛋白质作用学说，认为全麻统一在受体和通道水平上。目前公认的观点是全麻药主要作用于膜蛋白而非膜脂质，且仅与中枢神经系统中少数的作用靶位相结合而发挥作用，并进一步证实这些靶位主要是配体门控离子通道。全麻药通过该通道的有关受体发挥正性或负性调节作用。本文仅就全麻药对抑制性配体门控离子通道的作用做一综述。     

膜超极化激活离子通道及其靶向抗癫痫药物研究进展

癫痫是一种较为常见的神经系统疾病,主要以大量神经元同步异常放电为特征。目前普遍认为,神经元或神经网络兴奋性和抑制性电信号传输的失衡,是癫痫发病的最根本原因。现有的抗癫痫药物主要以钠离子通道、钙离子通道、钾离子通道、谷氨酸受体和γ-氨基丁酸离子通道为靶点,但接受这些药物治疗后,仍有近1/3的病人无法控制癫痫发作。因此,抗癫痫药物的研发亟需新靶点和新思路。许多研究证据表明,膜超极化激活离子通道的基因突变可以导致遗传型癫痫的发作,且在脑部损伤后,膜超极化激活离子通道会发生表达水平、通道生物物理学性质及通道亚基构成的改变,从而增加神经元和神经网络兴奋性,促使癫痫发病。故近年来,膜超极化激活离子通道及其靶向抗癫痫药物研究引起人们广泛关注。综述膜超极化激活离子通道与癫痫发病之间的关系,并探讨以膜超极化激活离子通道为靶点进行抗癫痫药物开发和治疗的可行性。     

抗癫痫药物及其非癫痫治疗用途

除癫痫外,抗癫痫药物也已显现对多种其它疾病治疗有益。这是因为涉及癫痫发作传播的离子通道、神经递质和神经受体等亦与其它中枢神经系统疾病如外周疼痛、偏头痛、焦虑症和双极症等症状表现相关,所以使用抗癫痫药物来治疗这些非癫痫疾病能够提供上述患者更多临床选择、甚或是满足现在远未满足的医学需求。本文将先就抗癫痫药物总体作一简述,而后在此基础上概要介绍它们用于治疗非癫痫疾病的临床研究进展。     

产后抑郁症治疗药物——zuranolone

zuranolone是一种神经活性类固醇,可作为γ-氨基丁酸（GABA）-A受体的正性变构调节剂。2023年8月4日,FDA批准zuranolone用于产后抑郁症（PPD）,这是首个用于治疗PPD的口服药物。临床研究结果显示,zuranolone对重度PPD患者抑郁症状的缓解率明显高于安慰剂组。但zuranolone可引起嗜睡、头晕和镇静,因此在服用期间应严密监测。本文就其作用机制、药动学、临床研究等进行概述。     

中医药调控神经递质治疗癫痫的研究进展

目前,癫痫的发病机制尚不明确,神经元中主要兴奋物谷氨酸(GLU)和主要抑制物γ-氨基丁酸(GABA)之间的变化在细胞兴奋性平衡中起着关键作用。由于不同的神经递质释放模式不同,并且存在时间和空间上的差异性,神经递质受体种类复杂及其分布和功能的不同,很多实验的关注点都集中在以GLU和GABA系统的研究上,而中医药对具体的神经递质合成、储存、释放、代谢等各环节并没有进行深入的研究。今后应在探索中医药治疗癫痫作用机制的基础上,进一步明确其对神经递质相互作用及变化的干预情况,以体现中医药的整体调控特色和稳定持久的作用效果。     

γ-氨基丁酸与哮喘的关系

γ-氨基丁酸(GABA)是哺乳动物中枢神经系统重要的抑制性神经递质之一,也存在于气道平滑肌细胞及气道上皮细胞等周围组织。研究表明,GABA系统与哮喘有密切关系。GABA受体主要分为A型和B型两类。GABAA受体激动剂蝇蕈醇能松弛由速激肽、组胺引起的气道平滑肌的收缩,并能减轻乙酰胆碱引起的气道通气压力增大;而GABAA受体抑制剂能抑制小鼠过敏性哮喘时杯状细胞增生及黏液过度分泌;GABAB受体激动剂可抑制神经诱导的胆碱能和速激肽介导的气道平滑肌收缩,微血管渗漏及过敏反应。由此可见,GABA系统可影响哮喘疾病发病过程中一些病理生理过程,因此GABA系统对治疗哮喘疾病具有重要价值。     

神经肽Y对海人酸致痫大鼠中GABAB受体的影响

目的 探讨重组腺相关病毒载体神经肽Y(rAAV2/1-NPY-EGF-P)干预前后海人酸致痫大鼠海马中GABABR表达的变化.方法 将36只雄性Wistar大鼠随机分为三组:KA组(海人酸致痫大鼠组)、NPY组(神经肽Y干预组)及NS组(对照组).KA组大鼠海马CA3区注射海人酸,完成慢性模型,造模成功后不注射病毒;NPY组大鼠海马CA3区注射海人酸,完成慢性模型,造模成功后向脑室注射10μL滴度为5×10u vg/mL的神经肽Y进行基因转染;NS组海马CA3区注射等量的0.9％NaCl.三组大鼠各12只,在基因转染后2周、4周分别取6只观察其发作行为学变化,并采用RT-PCR检测GABABR的表达,以GAPDH为标准参照基因,以之定量分析基因表达的RQ值(相对定量值).结果 通过RT-PCR发现,KA组、NPY组及NS组、海马组织均有GABABR表达.KA组GABABR的基因表达较NS组呈下降趋势(P＜0.05),NPY组GABABR的基因表达呈上升趋势,差异有统计学意义(P＜0.05).结论 KA组中GABABR的表达明显下降,NPY组中GABABR的表达呈上升趋势.说明GABABR基因表达的降低可能是导致癫痫发生、发展的重要因素.NPY可能通过改变抑制性神经递质的GAB-ABR的表达来达到调控癫痫发作的目的.     

儿童抗癫痫药物研究进展

目前,使用抗癫痫药物仍然是儿童癫痫治疗主要手段. 由于儿童处于快速生长发育阶段,其机体器官功能、药动学与成人显著不同,且选药、疗效评估、预后具有特殊性. 较成人而言,儿童由于大脑兴奋性和抑制性尚未达到平衡,更易罹患癫痫,且抗癫痫药物不合理使用也更易发生认知功能障碍. 如何合理应用抗癫痫药物,达到满意的治疗效果,已经引起广大医务工作者的广泛注意. 因此,不仅要遵循抗癫痫药物治疗原则选药、对患者进行定期疗效评估,还必须尽可能选择对认知功能损害小的抗癫痫药物,积极检测不良反应,这对儿童癫痫药物治疗具有重要意义.     

抗惊厥药物发展现状、研究进展和市场趋向

抗惊厥药物是主要用于治疗癫痫的一类药物,癫痫则为一种在全球影响到近5000万人的神经系统疾病。抗惊厥药物能够通过作用于突触中的各种分子靶的,包括电压门控钙通道、电压门控钠通道、A型γ-氨基丁酸（GABAA）受体和谷氨酸受体等,     

新型抗抑郁药物的研究进展

近年来对抑郁症发病机制和药物治疗靶标的研究取得了很大进展,围绕神经可塑性、神经发生、下丘脑-垂体-肾上腺(HPA)轴等后续神经系统适应性改变以及免疫系统变化,确定了谷氨酸受体、神经肽受体、糖皮质激素受体、褪黑激素受体和细胞因子受体等抗抑郁药物作用的新靶标。目前,已发现大量具有抗抑郁作用的新化合物,褪黑激素受体激动剂阿戈美拉丁、促肾上腺皮质激素释放激素受体拮抗剂喹硫平已经上市,神经激肽2受体拮抗剂沙瑞度坦、糖皮质激素受体拮抗剂米非司酮正在进行Ⅲ期临床研究,10余个药物进入临床研究阶段。本文对近5年新型抗抑郁药物的研究进展进行简要综述。     

谷氨酸在晕动病发病机制中的作用及相关药物研究

谷氨酸不仅是人和哺乳动物中枢神经系统的基本兴奋性神经递质,也参与外周感觉系统的突触传递。然而,过量谷氨酸引起的谷氨酸受体过度激活导致谷氨酸兴奋性神经毒性。本文对谷氨酸在前庭终器的神经传递和谷氨酸在晕动病中对其的兴奋毒性进行了讨论,并对与谷氨酸神经传递过程相关的抗晕动病药物进行综述。     

New anti-epileptic drugs

Epilepsy represents the most common serious neurological disorder, with a prevalence of 0.4 - 1%. Approximately 30% of patients are resistant to currently available drugs. New anti-epileptic drugs are needed to treat refractory epilepsy, improve upon current therapies, improve the prognosis of epilepsy and to prevent the epileptogenic process. Designing compounds with specific physiological targets would seem the most rational method of anti-epileptic drug development, but results from this approach have been disappointing; the widespread screening of compounds in animal models has been much more fruitful. Older methods of animal screening have used acute seizure models, which bear scant relationship to the human condition. More modern methods have included the development of animal models of chronic epilepsy; although more expensive, it is likely that these models will be more sensitive and more specific in determining anti-epileptic efficacy. In this review, we consider the possible physiological targets for anti-epileptic drugs, the animal models of epilepsy, problems with clinical trials and ten promising anti-epileptic drugs in development (AWD 131-138, DP16 (DP-VPA), ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, retigabine, rufinamide and soretolide). Perhaps the most important advances will come about from the realisation that epilepsy is a symptom, not a disease. Preclinical testing should be used to determine the spectrum of epilepsies that a drug can treat, and to direct later clinical trials, which need to select patients based on carefully defined epilepsy syndromes and aetiologies. Not only will such an approach improve the sensitivity of clinical trials, but also will lead to a more rational basis on which to treat.     

Limited P-glycoprotein mediated efflux for anti-epileptic drugs

A variety of anti-epileptic drugs (AEDs) were tested for their ability to be transported by P-glycoprotein (P-gp) through Caco-2 monolayers using bi-directional (apical (Ap) to basolateral (Bas), and Bas to Ap) studies. Transport rates were equivalent in both directions for vigabatrin, gabapentin, phenobarbitone, lamotrigine and carbamazepine, being 0.7 × 10^{? 6}, 0.1 × 10^{? 6}, 34 × 10^{? 6}, 36 × 10^{? 6} and 55 × 10^{? 6} cm/s, respectively. Phenytoin displayed a 20% increase in Ap to Bas transport, while topiramate and ethosuximide each had greater transport in the uptake direction, with both drugs showing no efflux. None of the transport rates for these drugs were affected by P-gp inhibitors. However, the efflux rate for acetazolamide was 3-fold higher than its uptake and this was significantly reduced by P-gp inhibitors. Thus, only one anti-epileptic, acetazolamide, was shown to be weak P-gp substrate, suggesting that P-gp efflux may not be a factor in relation to the development of resistance of epilepsy therapy.     

新型抗癫药物的治疗安全性

新型抗癫药物对皮肤结缔组织、心血管系统、消化系统、血液系统、神经系统、内分泌和代谢等多系统均可产生药物不良反应,甚至可能影响认知功能,致畸,加重癫症状。本文对新型抗癫药物的不良反应进行综述。     

New anti-epileptic drugs for the 21st century

Prior to 1993, there were only six major drugs available in the US for the treatment of patients with epilepsy. These included phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), primidone (PRIM), valproic acid/sodium valproate (VPA) and ethosuximide (ESX). Of these drugs, VPA has the broadest spectrum of activity and ESX the most limited. Despite these six agents, as well as several secondary drugs, it is estimated that over 30% of patients have inadequate seizure control, while others, whose disease is adequately controlled, suffer from bothersome adverse events (AEs). Since 1993, ten new drugs have entered the worldwide market (not all in the US). Those released include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LVT), zonisamide (ZNS), clobazam (CLB) and vigabatrin (VGB). The purpose of this article is to review each of the above drugs, looking at efficacy, safety, tolerability and where they may play a role in the current treatment of epilepsy.     

Model studies of the function of blockers on the small conductance potassium ion channel

Abstract: A correlation between K_I (equilibrium dissociation constants) and IC₅₀ (concentration at 50% inhibition) inhibitors for the family of blockers of the small conductance potassium ion channels and their intrinsic characteristics like molecular mass and volume have been investigated. Most of the blockers in the family are not selective, in contrast to apamin – an 18 amino acid bee venom toxin – that is known to be a highly potent and selective blocker of these channels. Differences and similarities between the blockers have been analyzed, pointing toward the origin of their selectivity and relative potency. In conclusion, an ion channel blocking is a process controlled mainly by diffusion, in accordance with previous experimental results.     

Development of individualized medicine for epilepsy based on genetic information

Despite the continuous development and release of new anti-epileptic drugs (AEDs), almost one in four patients are resistant to AED therapy. Current therapy requires trial and error to determine the most effective AED and dosage for a patient. The development of individualized medicine for epilepsy is critical for improving AED treatment, particularly that based on genetic information. However, several crucial issues remain to be resolved before the development of AED therapy can proceed further. The epilepsy genes responsible for common phenotypes have not yet been identified and ongoing pharmacogenetic studies continue to search for an explanation as to why 20–25% of patients do not respond to AEDs. There is no convincing clinical evidence that P-glycoprotein at the blood–brain barrier limits the uptake of AEDs into the brain of epileptic patients and contributes to the development of the drug-resistant phenotype. This article provides a critical review of the status and perspectives for the development of individualized medicine for epilepsy, based on genetic polymorphisms/mutations in relation to three major components: the pharmacodynamic pathway, the pharmacokinetic pathway and the mechanisms of action of AEDs. The development of multiplex assay technologies, together with the generation of epilepsy animal models bearing human epilepsy genes, are also discussed.     

Novel anticonvulsant drugs targeting voltage-dependent ion channels

Epilepsy is one of the most common neurological disorders with a prevalence of 0.5 – 1%. About two-thirds of epilepsy patients respond well to anticonvulsant pharmacotherapy and become seizure free. There is a third who remain pharmacoresistant, demonstrating the pressing need for novel treatment options that could be drugs with a different mechanism of action compared with those that are currently in clinical use. During the past, many new substances have been screened for blocking or activating effects on specific ion channels, particularly those that are not targets for currently used antiepileptic drugs. This review provides an overview of new anticonvulsant compounds targeting voltage-dependent ion channels.