Relation between rs2298771 genotype in voltage-gated sodium channels 1A polymorphism and antiepileptic drug response in children with epilepsy / 中华神经医学杂志

Objective:To investigate the relation between rs2298771 genotype in voltage-gated sodium channels 1A ( SCN1A) polymorphism and antiepileptic drug (AED) response in children with epilepsy. Methods:Sixty-two children with epilepsy admitted to Department of Neurology, Zhangjiakou First Hospital from June 2022 to December 2023 were divided into AED response group and AED resistance group ( n=31) according to their response to AED. In addition, 31 children with pharyngitis or mild gastroenteritis admitted to Department of Pediatrics at the same period were selected as control group. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze the rs2298771 genotype in SCN1A polymorphism, and differences in rs2298771 genotype and allele in SCN1A polymorphism were compared among the 3 groups. Relation between rs2298771 genotype in SCN1A polymorphism and AED response was analyzed. Multivariate Logistic regression was used to analyze the influencing factors for AED response in children with epilepsy. Results:(1) Significant differences in type of first seizure and AEDs were noted between AED response group and AED resistance group ( P<0.05); compared with the AED resistance group, the AED response group had significantly lower seizure frequency, significantly longer duration after last seizure, and statistically higher proportions of children with normal EEG or with one kind of AED ( P?0.05). (2) Compared with the control group and AED response group, the AED resistance group had significantly higher rs2298771 GC genotype and G allele, and statistically lower rs2298771 AA genotype and A allele in SCN1A polymorphism ( P?0.05). (3) In the AED response group, rs2298771 AA and AG genotype in SCN1A polymorphism were positively correlated with levetiracetam ( P?0.05); in AED resistance group, rs2298771 AG genotype in SCN1A polymorphism was positively correlated with topiramate and valproic acid ( P<0.05). (4) Multivariate Logistic regression analysis showed that duration after last seizure ( OR=3.249, 95% CI=1.097-9.621, P=0.033), rs2298771 genotype in SCN1A polymorphism ( OR=9.660, 95% CI=4.680-19.970, P=0.011) and seizure frequency ( OR=0.160, 95% CI=0.032-0.804, P=0.026) were independent influencing factors for AED response in children with epilepsy. Conclusion:Epilepsy children with shorter duration after last seizure, rs2298771 GG genotype in SCN1A polymorphism, and high seizure frequency are susceptible to AED resistance; especially, AG genotype is correlated with topiramate and valproic acid.

Research progress on potential therapeutic targets of chronic cough / 中国药理学通报

Chronic cough is caused by low levels of heat, mechanical or chemical exposure, which is characterized by the disorders of channels and receptors in neuroregulation such as the peripheral and central nerves. Potential regulatory targets of peripheral nerves include P2X3 receptors and transient receptor potential channels, while potential regulatory targets of central nerves include voltage-gated sodium channels, neurokinin-1 receptors, α-7acetylcholine receptors and gamma aminobutyric acid receptors. This paper focuses on the principle and clinical research evidence of several ongoing targeted therapy strategies, in order to provide new ideas for the development of drugs for the treatment of chronic cough.

Effects of repetitive transcranial magnetic stimulation on neuronal excitability and ion channels in hindlimb unloading mice / 生物医学工程学杂志

Weightlessness in the space environment affects astronauts' learning memory and cognitive function. Repetitive transcranial magnetic stimulation has been shown to be effective in improving cognitive dysfunction. In this study, we investigated the effects of repetitive transcranial magnetic stimulation on neural excitability and ion channels in simulated weightlessness mice from a neurophysiological perspective. Young C57 mice were divided into control, hindlimb unloading and magnetic stimulation groups. The mice in the hindlimb unloading and magnetic stimulation groups were treated with hindlimb unloading for 14 days to establish a simulated weightlessness model, while the mice in the magnetic stimulation group were subjected to 14 days of repetitive transcranial magnetic stimulation. Using isolated brain slice patch clamp experiments, the relevant indexes of action potential and the kinetic property changes of voltage-gated sodium and potassium channels were detected to analyze the excitability of neurons and their ion channel mechanisms. The results showed that the behavioral cognitive ability and neuronal excitability of the mice decreased significantly with hindlimb unloading. Repetitive transcranial magnetic stimulation could significantly improve the cognitive impairment and neuroelectrophysiological indexes of the hindlimb unloading mice. Repetitive transcranial magnetic stimulation may change the activation, inactivation and reactivation process of sodium and potassium ion channels by promoting sodium ion outflow and inhibiting potassium ion, and affect the dynamic characteristics of ion channels, so as to enhance the excitability of single neurons and improve the cognitive damage and spatial memory ability of hindlimb unloading mice.

Voltage-gated sodium channels gene expression in Burning Mouth Syndrome: a case-control study

Abstract Burning mouth syndrome (BMS) is a condition characterized by painful symptoms of the oral mucosa, despite the absence of any clinical signs. Its etiology is unknown, and there is still no effective treatment to date. Current evidence has shown neuropathic impairment in BMS patients. Neuropathic pain can be related to the dysfunction of voltage-gated sodium channels, considering that these receptors regulate the induction of action potentials in nociceptive neurons. This study evaluated the gene expression of voltage-gated sodium channels Na v 1.7, Na v 1.8 and Na v 1.9 in these patients. The gene expressions of these channels were assessed by real time RT-PCR analysis of fresh-frozen tongue biopsies in a case-control study composed of 12 patients with BMS, and 5 healthy control patients, proportionally matched by sex and age, and analyzed using the 2^(-Delta Delta CT) method. There was no statistically significant difference between the analyzed groups, despite the increase in Na v 1.7 (fold-change = 3.13, p = 0.52) and decrease in Na v 1.9 (fold-change = 0.45, p = 0.36) gene expression in the BMS group. The Na v 1.8 gene was not expressed in any of the samples analyzed. Although the gene expression in the voltage-gated sodium channels in BMS under study seems to be comparable with that of the normal oral mucosa, the functionality of these channels in BMS has not yet been identified, thus suggesting that further research is needed to better understand these voltage-gated sodium channels.

nNav1.5 expression is associated with glutamate level in breast cancer cells

Abstract Background: Glutamate and voltage-gated sodium channels, both have been the target of intense investigation for its involvement in carcinogenesis and progression of malignant disease. Breast cancer with increased level of glutamate often metastasize to other organs (especially bone), whilst re-expression of 'neonatal' Nav1.5, nNav1.5 in breast cancer is known to promote cell invasion in vitro, metastasis in vivo and positive lymph node metastasis in patients. Methods: In this study, the role of nNav1.5 in regulating glutamate level in human breast cancer cells was examined using pharmacological approach (VGSCs specific blocker, TTX, glutamate release inhibitor, riluzole and siRNA-nNav1.5). Effect of these agents were evaluated based on endogenous and exogenous glutamate concentration using glutamate fluorometric assay, mRNA expression of nNav1.5 using qPCR and finally, invasion using 3D culture assay. Results: Endogenous and exogenous glutamate levels were significantly higher in aggressive human breast cancer cells, MDA-MB-231 cells compared to less aggressive human breast cancer cells, MCF-7 and non-cancerous human breast epithelial cells, MCF-10A. Treatment with TTX to MDA-MB-231 cells resulted in significant reduction of endogenous and exogenous glutamate levels corresponded with significant suppression of cell invasion. Subsequently, downregulation of nNav1.5 gene was observed in TTX-treated cells. Conclusions: An interesting link between nNav1.5 expression and glutamate level in aggressive breast cancer cells was detected and requires further investigation.

Lidocaine in oncological surgery: the role of blocking in voltage-gated sodium channels. A narrative review / Lidocaína em cirurgia oncológica: o papel do bloqueio dos canais de sódio dependentes de voltagem. Revisão narrativa

Abstract Background: The current evidence suggests that oncological surgery, which is a therapy used in the treatment of solid tumors, increases the risk of metastasis. In this regard, a wide range of tumor cells express Voltage-Gated Sodium Channels (VGSC), whose biological roles are not related to the generation of action potentials. In epithelial tumor cells, VGSC are part of cellular structures named invadopodia, involved in cell proliferation, migration, and metastasis. Recent studies showed that lidocaine could decrease cancer recurrence through its direct effects on tumor cells and immunomodulatory properties on the stress response. Objective: The aim of this narrative review is to highlight the role of VGSC in tumor cells, and to describe the potential antiproliferative effect of lidocaine during the pathogenesis of metastasis. Contents: A critical review of literature from April 2017 to April 2019 was performed. Articles found on PubMed (2000-2019) were considered. A free text and MeSH-lidocaine; voltage-gated sodium channels; tumor cells; invadopodia; surgical stress; cell proliferation; metastasis; cancer recurrence - for articles in English, Spanish and Portuguese language - was used. A total of 62 were selected. Conclusion: In animal studies, lidocaine acts by blocking VGSC and other receptors, decreasing migration, invasion, and metastasis. These studies need to be replicated in humans in the context of oncological surgery.

Resumo Justificativa: As evidências atuais sugerem que a cirurgia oncológica, usada no tratamento de tumores sólidos, aumenta o risco de metástase. Nesse sentido, uma ampla gama de células tumorais expressa Canais de Sódio Dependentes de Voltagem (CSDV), cujos papéis biológicos não estão relacionados à produção de potencial de ação. Nas células epiteliais tumorais, o CSDV é parte integrante de estruturas celulares denominadas invadópodes, que participam da proliferação, migração e metástase celular. Estudos recentes mostraram que a lidocaína pode diminuir a recorrência do câncer através de efeitos diretos nas células tumorais e de propriedades imunomoduladoras na resposta ao estresse. Objetivo: O objetivo desta revisão narrativa é analisar o papel do CSDV nas células tumorais e descrever o possível efeito antiproliferativo da lidocaína na patogênese das metástases. Conteúdo: Foi realizada uma revisão crítica da literatura de Abril de 2017 a Abril de 2019. Os artigos encontrados no PubMed (2000 − 2019) foram analisados. Pesquisamos textos de linguagem livre e descritores MeSH-lidocaína; canais de sódio dependentes de voltagem; células tumorais; invadópodes; estresse cirúrgico; proliferação celular; metástase; recorrência do câncer − em artigos publicados em inglês, espanhol e português. Foram selecionadas 62 publicações. Conclusão: Em estudos empregando animais, a lidocaína atua bloqueando o CSDV e outros receptores, diminuindo a migração, invasão e metástase. Esses estudos precisam ser replicados em humanos submetidos a cirurgia oncológica.

Expression and Role of Voltage-Gated Sodium Channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7, Species Differences, and Regulation by Paclitaxel / 神经科学通报·英文版

Voltage-gated sodium channels (Navs) play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion (hDRG) tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Nav1.7 (~50% of total Nav expression) and lower expression of Nav1.8 (~12%), whereas the mouse DRG has higher expression of Nav1.8 (~45%) and lower expression of Nav1.7 (~18%). To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel (0.1-1 μmol/L) for 24 h. Paclitaxel increased the Nav1.7 but not Nav1.8 expression and also increased the transient Na currents and action potential firing frequency in small-diameter (<50 μm) hDRG neurons. Thus, the hDRG provides a translational model in which to study "human pain in a dish" and test new pain therapeutics.

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

BACKGROUND/AIMS: Patients with long-standing diabetes often demonstrate intestinal dysfunction and abdominal pain. However, the pathophysiology of abdominal pain in diabetic patients remains elusive. The purpose of study was to determine roles of voltage-gated sodium channels in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. METHODS: Diabetic models were induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in adult female rats, while the control rats received citrate buffer only. Behavioral responses to colorectal distention were used to determine colonic sensitivity in rats. Colon projection DRG neurons labeled with DiI were acutely dissociated for measuring excitability and sodium channel currents by whole-cell patch clamp recordings. Western blot analysis was employed to measure the expression of NaV1.7 and NaV1.8 of colon DRGs. RESULTS: STZ injection produced a significantly lower distention threshold than control rats in responding to colorectal distention. STZ injection also depolarized the resting membrane potentials, hyperpolarized action potential threshold, decreased rheobase and increased frequency of action potentials evoked by 2 and 3 times rheobase and ramp current stimulation. Furthermore, STZ injection enhanced neuronal sodium current densities of DRG neurons innervating the colon. STZ injection also led to a significant upregulation of NaV1.7 and NaV1.8 expression in colon DRGs compared with age and sex-matched control rats. CONCLUSIONS: Our results suggest that enhanced neuronal excitability following STZ injection, which may be mediated by upregulation of NaV1.7 and NaV1.8 expression in DRGs, may play an important role in colonic hypersensitivity in rats with diabetes.

The research progression of the voltage-gated sodium channels in tumor / 中国基层医药

Voltage-gated sodium channels are highly expressed in exciting cells,and play an important role in the depolarization of the membrane potential and the secretion and release of neurotransmitters.The recent research showed that the voltage gated sodium channels are highly expressed in colon cancer,breast cancer,prostate cancer and non-small cell lung cancer,and are closely associated with tumor proliferation,invasion,metastasis and other malignant biological behaviors.However,the mechanisms by which the ion channels regulate the biological behaviors and how the ion channels are mediated are still not clear.

Research progress in voltage-gated sodium channels and tumor / 肿瘤

Voltage-gated sodium channels (VGSCs) are heteromeric protein complexes containing one core subunit α and one or more auxiliary subunit β. VGSCs are widely expressed in various forms of tumor cells and tissues. Importantly, subunit α can regulate the invasive capacity of tumor cells, and subunit β is related to the adhesion and migration capacities of tumor cells. The function of subunit β in different types of tumor is different. Emerging studies have revealed that VGSCs have certain effects on tumor invasion and metastasis, which indicates that VGSCs may become the target for tumor diagnosis and targeted therapy. Therefore, this paper summarizes the effects of VGSCs on tumor invasion and migration, as well as the research progress in VGSCs used as tumor therapeutic target.

Role of NF-κB in diabetic neuropathy / 中国病理生理杂志

AIM: To investigate the role of NF-κB in diabetic neuropathy.METHODS: The diabetic rats were induced by intraperitoneal injection of streptozocin ( STZ) .The pain behavior test was used to detect the mechanical and thermal withdraw threshold of the rats’ bilateral hind paws.The protein levels of p-NF-κB and t-NF-κB in the rats’ L4 and L5 dorsal root ganglions ( DRG) were determined by Western blotting.The expression of Nav1.7 in DRG of diabetic neuropathy rats with or without NF-κB inhibitor PDTC was detected by the method of immunohistochemistry.RESULTS:The mechanical and thermal withdraw threshold of bilateral hind paws in the diabetic rats was decreased from 4 weeks to 12 weeks after injection of STZ.The protein levels of p-NF-κB in L4 and L5 DRG were significantly increased in the rats with diabetic neuropathy.Intrathecal administration of NF-κB inhibitor PDTC attenuated the increase in p-NF-κB and Nav1.7 in L4 and L5 DRG.Pain behaviors were also alleviated by PDTC.CONCLUSION:The increase in p-NF-κB is closely rela-ted to the generation of diabetic neuropathy.Inhibition of NF-κB blocks pain behaviors and the over-expression of Nav1.7 in DRG.

Functional Expression of Voltage-Gated Sodium Channels Navl.5 in Human Breast Caner Cell Line MDA-MB-231 / 华中科技大学学报（医学）（英德文版）

Voltage-gated sodium channels (VGSCs) are known to be involved in the initiation and progression of many malignancies,and the different subtypes of VGSCs play important roles in the metastasis cascade of many tumors.This study investigated the functional expression of Nav 1.5 and its effect on invasion behavior of human breast cancer cell line MDA-MB-231.The mRNA and pro-tein expression of Navl.5 was detected by real time PCR,Western Blot and immunofluorescence.The effects of Navl.5 on cell proliferation,migration and invasion were respectively assessed by MTT and Transwell.The effects of Nav1.5 on the secretion of matrix metalloproteases (MMPs) by MDA-MB-231 were analyzed by RT-PCR.The over-expressed Navl.5 was present on the membrane of MDA-MB-231 cells.The invasion ability in vitro and the MMP-9 mRNA expression were respec-tively decreased to (47.82±0.53)% and (43.97±0.64)% (P<0.05) respectively in MDA-MB-231 cells treated with VGSCs specific inhibitor tetrodotoxin (TTX) by blocking Navl.5 activity.It was con-eluded that Nav1.5 functional expression potentiated the invasive behavior of human breast cancer cell line MDA-MB-231 by increasing the secretion of MMP-9.