神经病理性疼痛与电压门控性钠离子通道机制研究的新进展

神经病理性疼痛是一种主要由外周或中枢神经感染、创伤、压迫、代谢障碍引起的难治性疼痛[1]。近来诸多学者研究发现在神经病理性疼痛的病理状态下,可能与钠离子、钙离子、钾离子等电压门控离子通道、受体、各种神经肽、酶、神经递质和细胞表面分子都有不同程度的上调或下调有     

电压门控钠通道亚型及相关疾病的研究进展

目的综述近年国内外电压门控钠通道亚型及相关疾病的研究新进展,为今后相关疾病的诊断和治疗提供理论依据。方法通过检索国内外相关文献,从钠通道的类别、亚型及相关疾病等方面进行综述。结果钠通道的主要作用是参与动作电位的形成和信号传导,临床许多疾病的发生和发展与钠离子通道的改变有关。钠通道结构或功能异常通常会导致如心血管系统、神经系统和肌肉等相关疾病的发生。结论不同类型的钠通道在机体生理病理过程中的不同环节发挥着不同的作用,近期研究取得了很大进展,其在相关疾病诊断和治疗方面的应用前景值得期待。     

电压门控钠通道在慢性疼痛药物发现中的研究进展

由于发病率高、药物效果有限或治疗药物受限等原因,慢性疼痛的治疗一直是世界范围内研究人员关注的难题。电压门控钠通道( VGSCs)阻滞剂有较为显著的镇痛作用,目前已知与慢性疼痛相关的钠通道亚型主要有 Nav1.3、Nav1.7、Nav1.8、 Nav1.9。2021年 8—9月进行了该研究,全面概括了上述钠通道亚型与慢性疼痛的关系,归纳出潜在候选药物临床前研究方法,以及已被证实安全有效的选择性钠通道阻滞剂品种,为选择性钠通道阻滞剂的开发提供参考。     

电压门控钠离子通道与疼痛

目的综述电压门控钠离子通道(voltage-gated sodium channels,VGSCs)与疼痛发生发展的相关性。方法根据已有的介绍电压门控钠离子通道与疼痛的文献共29篇,叙述不同α亚基与辅助亚基(β亚基)在疼痛发生与维持中的作用。结果特异性表达在外周神经系统中的钠离子通道NaV1.7、NaV1.8和NaV1.9,以及只在哺乳动物胚胎时期或神经元损伤后表达水平上调的NaV1.3与疼痛密切相关。结论 疼痛相关的电压门控钠离子通道亚型可作为疼痛性疾病治疗的药物筛选靶点。     

若干临床疾病与电压门控钠通道的特异调控

电压门控钠通道在细胞电兴奋活动中起着至关重要的调控作用.自19世纪40年代,Hodgkin等[1]首次定性地鉴定了兴奋性细胞膜钠通道的电生理活动特征,相当一段时期内,对钠通道分型的认识似乎主要依据其对河豚毒素(TTX)的药理敏感性,即TTX-敏感型(TTX-S)或TTX-非敏感型(TTX-R)钠通道.     

神经病理性疼痛动物模型

神经病理性疼痛动物模型的不断发展极大地促进了对神经病理性疼痛机制的研究。但是,目前的动物模型仍有很多缺陷,需要不断地完善,对疼痛的观察方法也需要改进。     

花生四烯酸对兔心室肌细胞电压门控钠通道的影响

目的研究花生四烯酸(AA)对兔心室肌细胞电压门控钠通道(VGSC)的影响。方法酶解法分离兔心室肌细胞,采用标准全细胞膜片钳技术记录电压门控钠通道电流(INa)。结果AA可浓度依赖性抑制INa,使INa的I-U曲线上移,但其激活电位、电位峰值和反转电位保持不变;AA使INa稳态失活曲线左移,恢复曲线右移;但对INa的抑制作用不具有明显的频率依赖性。结论AA对INa具有浓度依赖性抑制作用,主要是通过抑制失活和失活后恢复过程而发挥作用。因此AA对INa的抑制作用可能是AA抗心律失常,保护心肌的作用机制之一。     

电压门控钠离子通道与肿瘤

目的综述电压门控钠离子通道(voltage-gated sodium channels,VGSCs)在不同肿瘤发生、发展过程中的作用。方法根据已有的关于电压门控钠离子通道在不同肿瘤细胞中的表达有所不同,阐述VGSC与不同类型肿瘤发生、发展的相关性。结果侵袭性较强的肿瘤细胞中一般有特异性的VGSCα亚基的表达,而相应的侵袭性较弱的细胞中则无VGSC的表达。结论VGSC在肿瘤细胞中的异常表达,可作为治疗靶点而进行相关药物的开发和临床应用。     

电压门控钙离子通道药物研究进展

电压门控钙离子通道家族（VGCC）是细胞表面一类重要的信号转换器,它能够将膜电势转变成局部胞内钙离子瞬时变化,从而启动许多重要的生理活动,例如肌肉收缩、激素分泌、神经传递和基因表达。VGCC表达和功能的异常与高血压、心绞痛、心律失常、疼痛、癫痫和帕金森病等疾病的发生有很大关系。近年来,以VGCC为靶点的药物在临床上表现出良好的治疗效果和较小的不良反应,具有较好的应用前景。综述VGCC的结构、功能以及相关药物研究进展,以期为与VGCC相关的药物开发提供参考。     

电压门控钙离子通道的研究进展

电压门控钙离子通道(voltage-gated calcium channel)是一种镶嵌于细胞膜上的大分子蛋白复合体,其中央是高度选择性的亲水通道,允许适当电荷和适当大小的钙离子通过.钙离子通道广泛分布于机体的脑、心脏、平滑肌以及内分泌细胞等组织中,并在基因表达、肌肉收缩和荷尔蒙的释放等生命活动中扮演着重要角色.本文就电压门控钙离子通道的基因编码、生理分布及空间结构的研究进展综述如下.     

Sodium channel blockers for neuropathic pain

Importance of the field: The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability and their abnormal activity is related to several pathological processes, including cardiac arrhythmias, epilepsy, neurodegenerative diseases, spasticity, chronic and neuropathic pain. In particular, neuropathic pain (e.g., postherpetic and trigeminal neuralgia, diabetic neuropathy and spinal cord injury) is a serious clinical problem that affects a high percentage of the world population. Because an altered sodium channel isoform expression profile has been considered one reason for the changes in neuronal excitability, there is a continuous quest for new selective molecules targeting sodium channels for the treatment of chronic pain.

Areas covered in this review: PubMed, http://www.sciencedirect.com/, SciFinder^® Scholar and http://ep.espacenet.com/ were used as sources for this review and patents between 2007 and September 2009 were taken into account for the sodium channel blockers molecular classes reviewed and discussed herein.

What the reader will gain: The sodium channel blockers reported in this review have been categorized into different molecular classes on the basis of their wide structural diversity. This classification, somewhat arbitrary, does not necessarily reflect the presence of pharmacophoric elements but offers a useful way to discuss and comment on structurally homogenous classes of chemotypes recently patented.

Take home message: The continuous discoveries in the field of sodium channel blockers, highlighted by the increasing numbers of patent applications published in the last few years and by the numbers of compounds currently in clinical development, underline the importance of this target for the treatment of neuropathic pain. The great difficulty in the design of new selective and active structures, not obtained from old VGSC blockers that are often associated with high risk of adverse effects, is a strong challenge for medicinal chemistry research.     

Novel sodium channel antagonists in the treatment of neuropathic pain

Introduction: Effective and safe drugs for the treatment of neuropathic pain are still an unmet clinical need. Neuropathic pain, caused by a lesion or disease that affects the somatosensory system, is a debilitating and hampering condition that has a great economic cost and, above all, a tremendous impact on the quality of life. Sodium channels are one of the major players in generating and propagating action potentials. They represent an appealing target for researchers involved in the development of new and safer drugs useful in the treatment of neuropathic pain. The actual goal for researchers is to target sodium channels selectively to stop the abnormal signaling that characterizes neuropathic pain while leaving normal somatosensory functions intact.

Areas covered: This review covers the most recent publications regarding sodium channel blockers and their development as new treatments for neuropathic pain. The main areas discussed are the natural sources of new blockers, such as venom extracts and the recent efforts from many pharmaceutical companies in the field.

Expert opinion: There have been serious efforts by both the pharmaceutical industry and academia to develop new and safer therapeutic options for neuropathic pain. A number of different strategies have been undertaken; the main efforts directed towards the identification of selective blockers starting from both natural products or screening chemical libraries. At this time, researchers have identified and characterized selective compounds against Na_V1.7 or Na_V1.8 voltage-gated sodium channels but only time will tell if they reach the market.     

Blocking sodium channels to treat neuropathic pain

Neuropathic pain remains a large unmet medical need. A number of therapeutic options exist, but efficacy and tolerability are less than satisfactory. Based on animal models and limited data from human patients, the pain and hypersensitivity that characterize neuropathic pain are associated with spontaneous discharges of normally quiescent nociceptors. Sodium channel blockers inhibit this spontaneous activity, reverse nerve injury-induced pain behavior in animals and alleviate neuropathic pain in humans. Several sodium channel subtypes are expressed primarily in sensory neurons and may contribute to the efficacy of sodium channel blockers. In this report, the authors review the current understanding of the role of sodium channels and of specific sodium channel subtypes in neuropathic pain signaling.     

Voltage-gated sodium channels: the search for subtype-selective analgesics

Background: Primary afferent or sensory neurons innervate almost all the tissues of the body. They are vital in receiving sensory information and conveying this to the spinal cord and subsequently to the brain, where the higher centres convert this afferent input into an ‘understanding’ of its nature. The nociceptors are a subset of sensory neurons responsible for the transmission of ‘painful’ stimuli into the CNS. Objective/methods: Voltage-gated sodium channels (VGSCs) are pivotal in the transduction of noxious signals at the terminals of the nociceptors and the transmission of the signal along the axon and into the spinal cord and brain. There are nine functional members of the VGSC family. This review aims to briefly summarise the biology of the family, discuss those VGSCs involved in the transduction and transmission of nociceptive signals and to highlight the potential and also the challenges in seeking subtype-selective VGSC modulators for the effective treatment of pain. Results/conclusion: Robust evidence from preclinical models – and better yet, overwhelming human clinical genetic data – provides a compelling rationale for the involvement of VGSCs in nociceptive processing. Some compounds showing a low degree of subtype selectivity have been progressed into clinical development, but the results have been disappointing. It is likely that the high degree of structural homology within the VGSC family is a causative factor in making the discovery of subtype-selective modulators extremely challenging. A much greater understanding of the structure – function relationship for VGSCs and pharmacological modulators is needed if we are to design the compounds that will target those channels involved in nociceptive signalling whilst sparing those in the heart and brain. Only then will we be able to deliver a quantum leap in analgesic pharmacotherapy, providing the effective and well-tolerated drugs that the patient needs.     

Voltage-gated cation channel modulators for the treatment of stroke

Neuronal voltage-gated cation channels regulate the transmembrane flux of calcium, sodium and potassium. Neuronal ischaemia occurring during acute ischaemic stroke results in the breakdown in the normal function of these ion channels, contributing to a series of pathological events leading to cell death. A dramatic increase in the intracellular concentration of calcium during neuronal ischaemia plays a particularly important role in the neurotoxic cascade resulting in stroke-related acute neurodegeneration. One approach to provide therapeutic benefit following ischaemic stroke has been to target neuronal voltage-gated cation channels, and particularly blockers of calcium and sodium channels, for post-stroke neuroprotection. A recent development has been the identification of openers of large-conductance calcium- and voltage-dependent potassium channels (maxi-K channels), which hyperpolarise ischaemic neurons, reduce excitatory amino acid release, and reduce ischaemic calcium entry. Thus far, targeting these voltage-gated cation channels has not yet yielded significant clinical benefit. The reasons for this may involve the lack of small-molecule blockers of many neuronal members of these ion channel families and the design of preclinical stroke models, which do not adequately emulate the clinical condition and hence lack sufficient rigor to predict efficacy in human stroke. Furthermore, there may be a need for changes in clinical trial designs to optimise the selection of patients and the course of drug treatment to protect neurons during all periods of potential neuronal sensitivity to neuro-protectants. Clinical trials may also have to be powered to detect small effect sizes or be focused on patients more likely to respond to a particular therapy. The development of future solutions to these problems should result in an improved probability of success for the treatment of stroke.     

Voltage-gated Na+ channels in neuropathic pain

Neuropathic pain occurs as a result of some form of injury to the nervous system. Although the basis of the disease remains to be fully elucidated, numerous studies have suggested a major role for ion channels in the pathogenesis of neuropathic pain. As Na⁺ channels play a fundamental role in not only the generation but also in the conduction of an action potential, they have received considerable attention in the aetiology of pain sensation and have become important pharmacological targets. In this review, the authors discuss the importance of specific Na⁺ channel isoforms in the pathophysiology of neuropathic pain and the present use of Na⁺ channel antagonists in the treatment of neuropathic pain.     

Epilepsy and sodium channel blockers

Epilepsy is one of the most frequent neurological diseases and although most patients nowadays respond well to anti-epileptic drugs (AED), 30 - 40% of them still present seizures despite treatment with 2 or more AED. This illustrates the need for discovery and testing of new molecules designed for specific brain targets. Several voltage-gated Na⁺ channel gene mutations were shown to be associated with genetic and hereditary epilepsy. Thus, while it is noteworthy that some currently available AED act through Na⁺ channels, the identified mutations in Na⁺ channel genes strongly support the development of new Na⁺ channel blockers used as AED. This review focuses on the pathophysiology of epilepsy and particularly on insight gained from the identification of mutations in idiopathic epilepsy (IE). All of the IE mutations identified concern genes coding for ion channels, suggesting a possible role of these integral membrane proteins in epileptogenesis. The recent identification of mutations in genes encoding the α1, α2 and β1 subunits of the voltage-gated Na⁺ channel (SCN1A, SCN2A, SCN1B) and their association with febrile seizures (FS) further illustrates the contribution of these channels in epilepsy. Modes of action of AED supposed to act through the voltage-gated Na⁺ channels are examined in an attempt to propose alternative routes to discover new active compounds.     

神经痛的药物作用靶点及其机制

目的对近年来出现的治疗神经痛的药物作用靶点及其机制作以综述。方法在查阅30篇文献的基础上,对神经痛的治疗靶点进行整理和归纳。结果目前治疗神经痛的药物作用靶点主要有5-羟色胺受体、去甲肾上腺素受体、阿片受体、大麻素受体、离子通道、免疫相关物质等等。以这些靶点设计的药物均已证明可在一定程度上缓解神经痛。结论为进一步开发治疗神经痛的靶向药物提供参考。