Sodium Channel Receptor Research Articles

In-silico Studies, Design, and Synthesis of Pyrimidine-linked Benzothiazoles for its Anticonvulsant Potential.

The objective of the study was to design and synthesize a series of N-(6-substituted-1,3-benzothiazole- 2-yl)-2-{[6-(3-substitutedphenyl)-5-cyano-2-sulfanylpyrimidine-4-yl)]amino}acetamide derivatives BPD (1-15) that contains key pharmacophores required for anticonvulsant action. The titled compounds (BPD 1-15) were synthesized by reacting 2-substituted-N-(6-chlorobenzo[d]thiazol2-yl)acetamide with 4-amino-6-(4-substituted phenyl)-2-mercapto pyrimidine 5-carbonitrile in the presence of potassium carbonate and dry acetone. The synthesized compounds BPD (1-15) were assessed in vivo by the maximum electric shock (MES) test and the subcutaneous pentylenetetrazol (scPTZ) test in mice. The neurotoxicity test was performed by the rotarod test. A molecular docking study of title compounds with a sodium channel receptor (PDB ID: 1BYY) was carried out using the SP Docking protocol of the Glide module of the Maestro. Pharmacophore modeling was used to qualitatively identify the chemical characteristics for ligand binding and their spatial configurations in the 3D space of the active site. Among the studied compounds, BPD-15 and BPD-5 compounds showed significant action in both the MES and scPTZ models, with no neurotoxicity. BPD-15 & BPD-5 were relatively safe in acute toxicity testing. Compounds BPD-15 and BPD-5 showed good dock scores of -6.434 and -6.191, respectively. Thus, the compounds BPD-15 and BPD-5 have shown a considerable affinity towards the sodium channel as compared to the standard drug Riluzole. Compound BPD-14 showed good drug compatibility, and compounds BPD-1, BPD-2, BPD-11, BPD-12, BPD-13, BPD-14, BPD-15 showed good ADME values.

The utility of lidocaine in neonatal conviction syndrome

BACKGROUND: Lidocaine is a drug belonging to the local anesthetics; it is rapidly distributed in the body and metabolized in the liver. At commonly recommended doses, the therapeutic index of lidocaine remains very high and plasma concentrations remain largely below neurotoxic, cardiotoxic and other thresholds. It is used during various medical procedures, and in the nervous system it acts by binding to a specific site which is the sodium channel receptor of the neural membrane and blocking the passage of ions. The present study is of interest to know the potential usefulness of lidocaine in neonates with convulsive syndrome. In order to implement improvements in the treatment of those who need it. In this way, pediatric neurologists can achieve better results in the interventions to treat this pathology. Methods: In the present systematic review we try to answer and perform a literature search through pubmed and others to analyze the usefulness of lidocaine in neonatal convulsive syndrome and its potential benefit. Results: After the application of the inclusion and exclusion criteria, we will be able to identify the groups of newborns most at risk and the efficacy of lidocaine treatment. Conclusion: It is concluded that lidocaine is the third drug used in neonatal convulsive syndrome for maintenance where it is received as a continuous infusion and is effective in suppressing electroclinical seizures; excessive doses should be avoided as it can also produce convulsions and other adverse effects in children.

Anticonvulsant effect of (±) citronellal possibly through the GABAergic and voltage-gated sodium channel receptor interaction pathways: In vivo and in silico studies

This study aimed to investigate the anticonvulsant effects of citronellal (CIT) and possible underlying mechanisms through an isoniazid (INH)-induced seizure (convulsion) via in vivo and in silico studies. For this, convulsions were induced by the oral administration of INH (300 mg/kg) to the mice. The animals were treated orally with different doses of CIT (50, 100, and 200 mg/kg). Vehicle served as a negative control (NC), while diazepam (DZP) (2 mg/kg) and carbamazepine (CAR) (80 mg/kg) were provided (p.o.) as positive controls (PC). A combination therapy of CIT (middle dose) with DZP and CAR was also given to two separate groups of animals to estimate the synergistic or antagonistic effects. Molecular docking and visualization of ligand-receptor interactions are also estimated through different computational tools. The results of the in vivo study showed that CIT dose-dependently significantly (p < 0.05) exhibited a higher onset of seizures while reducing the frequency and duration of seizures in mice compared to the NC group. Besides these, in combination therapy, CIT significantly antagonized the activity of CAR and DZP, leading to a reduction in the onset of seizures and an increase in their frequency and duration compared to treatment with CAR and DZP alone. Additionally, molecular docking revealed that the CIT exhibited a moderate binding affinity (−5.8 kcal/mol) towards the GABAA receptor and a relative binding affinity (−5.3 kcal/mol) towards the voltage-gated sodium channel receptor by forming several bonds. In conclusion, CIT showed moderate anticonvulsant activity in INH-induced convulsion animals, possibly by enhancing GABAA receptor activity and inhibiting the voltage-gated sodium channel receptor.

Myzus persicae (Sulzer, 1776) (Hemiptera: Aphididae) popülasyonlarında neonikotinoid ve sentetik piretroid insektisitlerin tekli ve karışımlarına karşı direnç durumu

The peach potato aphid, Myzus persicae (Sulzer, 1776) (Hemiptera: Aphididae), a vector of many plant virus diseases, causes damage to its wide range of hosts by direct feeding. Chemical control has been the primary method to control this species, and the intensive use of insecticides has led to the development of resistance. In this study, conducted between the years 2017-2019, firstly resistance ratio of five M. persicae populations from Antalya, Türkiye were determined by leaf-dip bioassay method. The field populations showed significant resistance to thiamethoxam (between 201-332 fold) and lambda-cyhalothrin (between 50-103 fold) when compared to susceptible population. To identify whether resistance mediated by mutations in sodium channel and nicotinic acetylcholine receptor, DNA regions that encompass “mutation hot-spot” were sequenced. This revealed no population contained R81T mutation that has been previously linked with neonicotinoid resistance. As to synthetic pyrethroid resistance, the L1014F kdr mutation was fixed in all field populations. This study is the first description of kdr mutation in M. persicae populations from Türkiye. Bioassay results also indicated that the toxicity of thiamethoxam and lambda-cyhalothrin mixture was higher than that of lambda-cyhalothrin alone. Our findings can make significant contributions to M. persicae resistance management.

1557MO Phase II trial evaluating effect of gonyautoxins (GTX), a paralytic shellfish poisoning (PSP) on objective and subjective symptoms of chemotherapy-induced peripheral neuropathy (CIPN)

CIPN is a common side-effect of anti-neoplastic drugs with no level 1 supportive treatment (Tx) approvals. Management of the adverse event (AE) is restricted to dose reductions and Tx interruptions. GTX is a PSP phycotoxin that reversibly binds voltage-gated sodium channel receptor sites on excitable cells, inhibiting membrane depolarization and nerve impulse conduction. Initial data indicates that GTX (topical formulation) improves PN-symptoms related to anti-HIV drugs. The aim of this study is to evaluate the effect of GTX on sensory symptoms of pts with grade 2 or higher (G≥2) CIPN.

Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases.

Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets.

Whole-genome sequencing to detect mutations associated with resistance to insecticides and Bt proteins in Spodoptera frugiperda.

The fall armyworm (FAW), Spodoptera frugiperda, is a major pest native to the Americas that has recently invaded the Old World. Point mutations in the target-site proteins acetylcholinesterase-1 (ace-1), voltage-gated sodium channel (VGSC) and ryanodine receptor (RyR) have been identified in S. frugiperda as major resistance mechanisms to organophosphate, pyrethroid and diamide insecticides respectively. Mutations in the adenosine triphosphate-binding cassette transporter C2 gene (ABCC2) have also been identified to confer resistance to Cry1F protein. In this study, we applied a whole-genome sequencing (WGS) approach to identify point mutations in the target-site genes in 150 FAW individuals collected from China, Malawi, Uganda and Brazil. This approach revealed three amino acid substitutions (A201S, G227A and F290V) of S. frugiperda ace-1, which are known to be associated with organophosphate resistance. The Brazilian population had all three ace-1 point mutations and the 227A allele (mean frequency = 0.54) was the most common. Populations from China, Malawi and Uganda harbored two of the three ace-1 point mutations (A201S and F290V) with the 290V allele (0.47-0.58) as the dominant allele. Point mutations in VGSC (T929I, L932F and L1014F) and RyR (I4790M and G4946E) were not detected in any of the 150 individuals. A novel 12-bp insertion mutation in exon 15 of the ABCC2 gene was identified in some of the Brazilian individuals but absent in the invasive populations. Our results not only demonstrate robustness of the WGS-based genomic approach for detection of resistance mutations, but also provide insights for improvement of resistance management tactics in S. frugiperda.

De novo transcriptome and expression profile analyses of the Asian corn borer (Ostrinia furnacalis) reveals relevant flubendiamide response genes

BackgroundThe Asian corn borer (ACB), Ostrinia furnacalis (Guenée), has become the most damaging insect pest of corn in Asia. However, the lack of genome or transcriptome information heavily hinders our further understanding of ACB in every aspect at a molecular level and on a genome-wide scale. Here, we used the Ion Torrent Personal Genome Machine (PGM) Sequencer to explore the ACB transcriptome and to identify relevant genes in response to flubendiamide, showing high selective activity against ACB.ResultsWe obtained 35,430 unigenes, with an average length of 716 bp, representing a dramatic expansion of existing cDNA sequences available for ACB. These sequences were annotated with Non-redundant Protein (Nr), Gene Ontology (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to better understand their functions. A total of 31 cytochrome P450 monooxygenases (P450s), 27 carboxyl/cholinesterases (CCEs) and 19 glutathione S-transferases (GSTs) were manually curated to construct phylogenetic trees, and 25 unigenes encoding target proteins (acetylcholinesterase, nicotinic acetylcholine receptor, gamma-aminobutyric acid receptor, glutamate-gated chloride channel, voltage-gated sodium channel and ryanodine receptor) were identified. In addition, we compared and validated the differentially expressed unigenes upon flubendiamide treatment, revealing that the genes for detoxification enzymes (P450s and esterase), calcium signaling pathways and muscle control pathways (twitchin and tropomyosin), immunoglobulin (hemolin), chemosensory protein and heat shock protein 70 were significantly overexpressed in response to flubendiamide, while the genes for cuticular protein, protease and oxidoreductase showed much lower expression levels.ConclusionThe obtained transcriptome information provides large genomic resources available for further studies of ACB. The differentially expressed gene data will elucidate the molecular mechanisms of ACB in response to the novel diamide insecticide, flubendiamide. In particular, these findings will facilitate the identification of the genes involved in insecticide resistance and the development of new compounds to control the ACB.

Studies on the mode of action of neurotoxic insecticides.

Many of the commercially available insecticides target the nervous system of insects, which are important targets of insecticides. We investigated the mechanism of action of the compound acts on voltage-sensitive sodium channel (Vssc) and nicotinic acetylcholine receptor (nAChR), and the associated mechanism of resistance, mainly using an electrophysiological method. The mechanism of resistance to pyrethroids in A. aegypti, that to neonicotinoids in A. gossypii, and the mechanism of action of the natural product asperparaline A were clarified. We also demonstrated that similar compounds that interacted on the same target with slightly different substituents exhibited different effects on the target molecule with different amino acid residues at the activity site, and that natural products exhibited specific activity and selectivity to insect ion channels.

Molecular sieves promoted, ultrasound-mediated synthesis, biological evaluation and docking study of 3-(5-substituted-1,3,4-thiadiazol-2-ylimino)indolin-2-ones as a potential anticonvulsant agents

In this work, the combined use of ultrasonic energy and molecular sieves was investigated for synthesis of 3-(5-substituted-1,3,4-thiadiazol-2-ylimino)indolin-2-one derivatives 5(a–j). The equimolar quantities of 5-substituted-1,3,4-thiadiazol-2-amine and isatin were sonicated in the presence of activated molecular sieves 3 A at a temperature of 50 °C and at a frequency 20 kHz, and higher yields (73–92 %) and faster reaction times (43–75 min) were obtained when ultrasonic irradiation was used in comparison with conventional methods. The synthesized compounds were evaluated for anticonvulsant (MES and sc-PTZ model) and behavioral activity (actophotometer) in mice. The compounds 5b, 5i and 5j have shown protection against MES model at 0.5- and 4-h period at dose level of 100 mg/kg, while the compound 5c showed protection against sc-PTZ model at the same dose level. To exploit the mode of action of the synthesized compounds, docking study against sodium channel receptor was performed and the results revealed good binding interactions with the receptor. ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.

Mesoscale infraslow spontaneous membrane potential fluctuations recapitulate high-frequency activity cortical motifs.

Neuroimaging of spontaneous, resting-state infraslow (<0.1 Hz) brain activity has been used to reveal the regional functional organization of the brain and may lead to the identification of novel biomarkers of neurological disease. However, these imaging studies generally rely on indirect measures of neuronal activity and the nature of the neuronal activity correlate remains unclear. Here we show, using wide-field, voltage-sensitive dye imaging, the mesoscale spatiotemporal structure and pharmacological dependence of spontaneous, infraslow cortical activity in anaesthetized and awake mice. Spontaneous infraslow activity is regionally distinct, correlates with electroencephalography and local field potential recordings, and shows bilateral symmetry between cortical hemispheres. Infraslow activity is attenuated and its functional structure abolished after treatment with voltage-gated sodium channel and glutamate receptor antagonists. Correlation analysis reveals patterns of infraslow regional connectivity that are analogous to cortical motifs observed from higher-frequency spontaneous activity and reflect the underlying framework of intracortical axonal projections.

Ultrasound-assisted synthesis, anticonvulsant activity, and docking study of indole-appended thiazolidin-4-ones.

Two series of novel indolyl thiazolidin-4-one derivatives 4a-j and 5a-j were obtained by an ecofriendly synthetic protocol by treating a mixture of Schiff's bases (0.01 mol) with thioglycolic acid or thiolactic acid (0.01 mol) and anhydrous zinc chloride in catalytic amount in DMF as solvent under ultrasound irradiation, using an ultrasound synthesizer with a synthetic solid probe. The structures of the synthesized compounds were confirmed by IR, (1) H NMR, (13) C NMR, MS, and elemental analysis. The anticonvulsant activity and neurotoxicity of the newly synthesized compounds were established by MES and sc-PTZ model and by rotarod test, respectively, in vivo using mouse models. The actophotometer was used for the screening of behavioral activity. The compounds exhibited promising anticonvulsant activity; especially, the compounds showed maximum protection in the MES model at a dose of 100 mg/kg. Further, docking studies of the synthesized compounds were performed against the sodium channel receptor and showed good binding interactions with the receptor. A computational study was carried out to highlight the pharmacophore distance mapping, log p determination, and pharmacokinetic parameters.

Ghrelin Gly90Leu and Ghrelin Receptor Gly57Gly Gene Variants Are Not Associated with Saltiness Intensity Perception and Pleasantness Ratings

Aims: The salty taste modality is modulated by epithelial sodium channel (ENaC) and Transient Receptor Potential Vanniloid (TRPV1) ionic channel and more recently, the gastric hormone ghrelin and its signaling system are also thought to play a role. Taste perception plays an important role in modulating food preference, and intake and is partly determined by genetic variations in chemoreceptor genes. For the salty taste modality, no studies have yet identified any genetic determinants of salt taste in humans. Nevertheless, a single study has identified that common variations in genes encoding for TRPV1 (TRPV1) and ENaC (SCNN1B) may influence the perception of salt solutions in humans, while it is currently unknown whether it would be the same for ghrelin and its cognate receptor, GHSR. Therefore, the primary objective of this study was to investigate the association of Ghrelin Gly90Leu and GHSR Gly57Gly gene polymorphisms with individual’s saltiness intensity perception and pleasantness ratings. Study Design: A convenience sampling method was practiced in this study. The sampling was carried out among students between the age of 18–25. Place and Duration of Study: Universiti Tunku Abdul Rahman (UTAR), Perak campus, Original Research Article European Journal of Nutrition & Food Safety, 4(2): 87-99, 2014 88 between January to December, 2011. Methodology: We recruited 166 Malaysian university students (mean age: 20.33±1.68; 75 males, 91 females; 152 ethnic Chinese, 14 Indians; 113 normal weight, 53 overweight) by convenience sampling. Low and high sodium concentrations of foods, solutions and broths were tasted and rated for their perceived intensity and pleasantness using generalized Labeled Magnitude Scale and Labeled Affective Magnitude scale, respectively. Results: The minor allele frequencies (MAF) of Ghrelin Gly90Leu and GHSR Gly57Gly were 0.48 and 0.31, respectively. Only the perceived intensity of salted egg was significantly different among Ghrelin Gly90Leu genotypes, where the individuals with T318T and A318T genotypes rated the intensity significantly higher than those with the A318A genotype. Conclusion: In conclusion, Ghrelin Gly90Leu and GHSR Gly57Gly SNPs did not serve as markers for individual’s saltiness intensity perception and pleasantness ratings, at least among Malaysian subjects in this study. This suggests that the ghrelin signaling mechanism in modulating salty taste responsivity in inconclusive at the moment, as the positive findings in mice might not be translatable to humans.

Sporadic pseudohypoaldosteronism: A challenging diagnosis

Introduction: Pseudohypoaldosteronism (PHA) is a rare form of salt-wasting syndrome, caused by peripheral resistance to aldosterone. PHA is of three types: PHA type 1, 2, 3. Pseudohypoaldosteronism type 1 (PHA_1) is further differentiated into, (i) hereditary forms, autosomal recessive and dominant, which are caused by epithelial sodium channel and mineralocorticoid receptor mutations respectively and (ii) secondary form which is associated with urological problems. Case Report: We present a case of a male infant who presented with failure to thrive, vomiting, mild dehydration and reflux. Evaluation revealed hyperkalemia with normal glucose and carbon dioxide levels. A preliminary diagnosis of CAH (congenital adrenal hyperplasia) was made. Further workup showed high serum aldosterone and renin levels with normal renal and adrenocortical functions. In line with the investigations the diagnosis of pseudohypoaldosteronism was made. The patient was treated with sodium supplementation, which normalized his clinical state and serum electrolytes. Follow-up revealed weight gain and improved status. Conclusion: Diagnosis of PHA_1 is based on plasma electrolyte assessment, elevated renin activity and aldosterone levels with normal renal function. PHA_1 results from a renal or systemic resistance to aldosterone. In our reported patient we suspected a renal form of PHA_1, which is a milder form and responded well to treatment with salt supplements. Infants who present with electrolyte imbalance like hyperkalemia, hyponatremia and weight loss should be evaluated for adrenocortical function and need careful management. Though PHA is a group of rare syndromes, a high degree of suspicion along with extensive laboratory workup should be pursued in cases with electrolyte imbalances.

反向药理学和基于传统药物的现代镇痛药的研发

疼痛是许多急慢性疾患中皆可出现的症状，它是危及人类健康及防碍正常生活的主要问题之一。为了抗御疼痛，人类一直在孜孜不倦地寻求镇痛药物。目前临床上使用最多的镇痛药是以吗啡为代表的阿片生物碱类及其合成代用品(或称阿片类药物——opioids)和非甾体抗炎药(Nonsteroidal Antiinflammatory Drugs，NSAIDs)，它们都有较为严重的毒、副作用。一些致痛因子和炎性介质，如5-HT，ATP，BK，His，PGE2，SP等，其相应的受体阻断剂的应用对于镇痛虽有一定效应，但由于此等受体分布广泛，故选择性作用部位不强而且副作用也较多。因此关注的焦点主要集中在探索表达于中、小直径的初级感觉神经元的河豚毒素不敏感型(tetrodotoxin-resistant，TTX-R)钠通道和瞬时感受器电位香草酸受体1(transient potential vanilloid receptor1，TRPV1)。遗憾的是多年来在这方面并无突破性进展。以植物为本的各民族传统药物是当今国际药品市场的潜在丰富来源。遵循“反向药理学”的研究模式，形成先导物发现可践行的方法学，结合先进的科学技术和方法，从长期临床应用证实具有较显著镇痛功效和较少毒、副作用的传统药物中提取、分离多种单体化学成分，对其进行系统的药理研究，开发出化学结构和镇痛机理明确、安全性高的新型镇痛药物，将是镇痛药研发中具有较高效率的新途径。在我们的研究中，发现了两种对TTX-R钠通道和TRPV1均具有调制作用的民族药物——龙血竭和野木瓜。这两种药物在临床上都有较好的镇痛疗效，并且无成瘾性方面的记录。我们还确定了龙血竭调制TTX-R钠通道和TRPV1的药效物质基础是其化学成分剑叶龙血素A、剑叶龙血素B和龙血素B的组合。 Pain is a major symptom in many medical conditions, and can significantly interfere with a person’s quality of life and general function. To relieve pain, people are unwearied to look for the analgesic drugs. Nowadays, the most popular analgesics in clinic practice are opioids and non-steroidal anti-inflammatory drugs (NSAIDs), both of which have some adverse reactions. Although the antagonists of some painful factor such as 5-HT, ATP, BK, His, PGE2 and SP receptors can relieve pain to some extent, they have some unpleasant side-effects and low selectivity for analgesic sites due to the wide distribution of them. Therefore, the focus of the research was concentrated on tetrodotoxin-resis- tant (TTX-R) sodium channel and transient potential vanilloid receptor 1(TRPV1) distributed in small-to-medium-sized primary sensory neurons. However, little breakthrough has been made for the past many years. The plentiful plant-derived national traditional medicine are potential resource of international pharmaceutical market nowadays. Based on the research framework of reverse pharmacology, combined with advanced science technique and methods, shaping into feasible methodology of discovering lead compounds, a new approach of developing analgesics is to ex- tract and separate various monomers from traditional medicine which have been confirmed significant efficacy and low side effect in clinic practice for a long period. The monomers will then be investigated systematically and developed into new analgesics with identified chemicial construction, clear-cut mechanism and high security. Our study discovered that two ethnodrugs, Dragon’s Blood Resin and Stauntonia chinensis DC., could interfere with pain messages and modulate TTX-R sodium and TPVR1 channels. They could produce excellent analgesic therapy in clinic without drug addiction. Moreover, the material basis for the modulation on TTX-R sodium channel and TPVR1 of Dragon’s Blood Resin was successfully validated to be the effective combination of cochinchinenin A, cochinchinenin B and loureirin B.

Angiotensin II Stimulates Renin in Inner Medullary Collecting Duct Cells via Protein Kinase C and Independent of Epithelial Sodium Channel and Mineralocorticoid Receptor Activity

Collecting duct (CD) renin is stimulated by angiotensin (Ang) II, providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates the epithelial sodium channel via the Ang II type 1 receptor and increases mineralocorticoid receptor activity attributed to increased aldosterone release. Our objective was to determine whether CD renin augmentation is mediated directly by Ang II type 1 receptor or via the epithelial sodium channel and mineralocorticoid receptor. In vivo studies examined the effects of epithelial sodium channel blockade (amiloride; 5 mg/kg per day) on CD renin expression and urinary renin content in Ang II-infused rats (80 ng/min, 2 weeks). Ang II infusion increased systolic blood pressure, medullary renin mRNA, urinary renin content, and intrarenal Ang II levels. Amiloride cotreatment did not alter these responses despite a reduction in the rate of progression of systolic blood pressure. In primary cultures of inner medullary CD cells, renin mRNA and (pro)renin protein levels increased with Ang II (100 nmol/L), and candesartan (Ang II type 1 receptor antagonist) prevented this effect. Aldosterone (10(-10) to 10(-7) mol/L) with or without amiloride did not modify the upregulation of renin mRNA in Ang II-treated cells. However, inhibition of protein kinase C with calphostin C prevented the Ang II-mediated increases in renin mRNA and (pro)renin protein levels. Furthermore, protein kinase C activation with phorbol 12-myristate 13-acetate increased renin expression to the same extent as Ang II. These data indicate that an Ang II type 1 receptor-mediated increase in CD renin is induced directly by Ang II via the protein kinase C pathway and that this regulation is independent of mineralocorticoid receptor activation or epithelial sodium channel activity.

Effects of Lidocaine Patch on Intradermal Capsaicin-Induced Pain: A Double-Blind, Controlled Trial

This study evaluated the effects of topical lidocaine on skin sensation and on intradermal capsaicin-induced pain and hyperalgesia. A randomized, double-blinded, placebo controlled methodology was used. After baseline sensory testing, a placebo patch and a lidocaine patch were randomized to the volar aspect of the left or right forearm for 4 hours. The right forearm patch was removed, the sensory testing was repeated, and capsaicin was injected intradermally at the site. Pain scores were measured at the time of injection and every 2.5 minutes for 10 minutes followed by measurement of the hyperalgesic area to von Frey hair and stroking, flare response, and repeat sensory testing. At the completion of the testing on the right forearm, the left forearm patch was removed and the procedures described for the right forearm were repeated for the left forearm. There was a significant reduction in cool sensation, warm sensation, and touch thresholds in the lidocaine but not placebo patch arm. The lidocaine patch had no significant effect on hot pain or mechanical pain thresholds. Intradermal capsaicin resulted in a significant decrease in hot pain and mechanical pain thresholds; however, lidocaine was unable to significantly reverse the thermal or mechanical hyperalgesia induced by capsaicin. The lidocaine patch did not reduce flare area, nor areas of hyperalgesia or allodynia. This study suggests that the sodium channels and the capsaicin receptors function independently to control peripheral terminal depolarization. The sodium channel and the transient receptor potential vanilloid 1 (TRPV1) receptor coexist on peripheral terminals of unmyelinated fibers. This study showed that activation of the TRPV1 receptor can depolarize the fibers in the presence of sodium channel blockade. This suggests that the sodium channel and TRPV1 receptor function independently in depolarizing the fibers.

Study of the binding residues between ANEPII and insect sodium channel receptor

The present study aimed at determining the functional characteristics of anti-neuroexcitation peptide II (ANEPII). The depressant insect toxin ANEPII from the Chinese scorpion Buthus martensii Karsch had an effect on insect sodium channels. Previous studies showed that scorpion depressant toxins induce insect flaccid paralysis upon binding to receptor site-4, so we tried to predict the functional residues involved using computational techniques. In this study, three-dimensional structure modeling of ANEPII and site-4 of the insect sodium channel were carried out by homology modeling, and these models were used as the starting point for nanosecond-duration molecular dynamics simulations. Docking studies of ANEPII in the sodium channel homology model were conducted, and likely ANEPII binding loci were investigated. Based on these analyses, the residues Tyr34, Trp36, Gly39, Leu40, Trp53, Asn58, Gly61 and Gly62 were predicted to interact with sodium channel receptor and to act as functional residues.

Ion Channel Blockers for the Treatment of Neuropathic Pain

Neuropathic pain, a severe chronic pain condition characterized by a complex pathophysiology, is a largely unmet medical need. Ion channels, which underlie cell excitability, are heavily implicated in the biological mechanisms that generate and sustain neuropathic pain. This review highlights the biological evidence supporting the involvement of voltage-, proton- and ligand-gated ion channels in the neuropathic pain setting. Ion channel modulators at different research or development stages are reviewed and referenced. Ion channel modulation is one of the main avenues to achieve novel, improved neuropathic pain treatments. Voltage-gated sodium and calcium channel and glutamate receptor modulators are likely to produce new, improved agents in the future. Rationally targeting subtypes of known ion channels, tackling recently discovered ion channel targets or combining drugs with different mechanism of action will be primary sources of new drugs in the longer term.

Epigenetic Gene Silencing Underlies C-Fiber Dysfunctions in Neuropathic Pain

Peripheral nerve injury causes neuropathic pain, which is characterized by the paradoxical sensations of positive and negative symptoms. Clinically, negative signs are frequently observed; however, their underlying molecular mechanisms are largely unknown. Dysfunction of C-fibers is assumed to underlie negative symptoms and is accompanied by long-lasting downregulation of Na(v)1.8 sodium channel and mu-opioid receptor (MOP) in the dorsal root ganglion (DRG). In the present study, we found that nerve injury upregulates neuron-restrictive silencer factor (NRSF) expression in the DRG neurons mediated through epigenetic mechanisms. In addition, chromatin immunoprecipitation analysis revealed that nerve injury promotes NRSF binding to the neuron-restrictive silencer element within MOP and Na(v)1.8 genes, thereby causing epigenetic silencing. Furthermore, NRSF knockdown significantly blocked nerve injury-induced downregulations of MOP and Na(v)1.8 gene expressions, C-fiber hypoesthesia, and the losses of peripheral morphine analgesia and Na(v)1.8-selective blocker-induced hypoesthesia. Together, these data suggest that NRSF causes pathological and pharmacological dysfunction of C-fibers, which underlies the negative symptoms in neuropathic pain.