Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons / 神经科学通报·英文版

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.

Evaluación de primers reportados para detección de KDR en especies de Anopheles colectadas en los departamentos de Caaguazú y Alto Paraná en Paraguay / Evaluation of primers reported for KDR detection in Anopheles species collected in the departments of Caaguazú and Alto Paraná in Paraguay

Las mutaciones KDR en el gen del canal del sodio (VGSC) han sido ya detectadas en al menos 13 especies de mosquitos Anopheles en su mayoría especies de África, pero aún resta por determinar los cebadores específicos para la detección en especies de Latinoamérica. En nuestro país la especie Anopheles darlingi es el vector principal de la malaria, y el A. albitarsis, el vector secundario. Se emplearon muestras de mosquitos Anoheles de las especies A. strodei, A. albitarsis, A. fluminensis, A. evansae, A. nuneztovari, A. nyssorhynchela lutzi y A. oswaldoi capturadas en los departamentos de Caaguazú y Alto Paraná en Paraguay. Para la amplificación y secuenciación se usaron cebadores reportados para el gen VGSC de A. albimanus en Guatemala, que resultaron ser específicos solo para la especie A. strodei. La secuencia revela el codón TTA que codifica para una Leucina como la secuencia TTG, reportada para la versión susceptible en la posición L1014. El fragmento amplificado es de aproximadamente 225 pares de bases. A nuestro entender, esta es la primera caracterización del gen VGSC en mosquitos Anopheles del Paraguay y para la especie A. strodei

KDR mutations in the sodium channel gene (VGSC) have already been detected in at least 13 species of Anopheles mosquitoes, mostly African species, but the molecular techniques for detection in Latin American species have yet to be determined. In our country, Anopheles darlingi species is the main vector of Malaria, and A. albitarsis, the secondary vector. We used samples of Anoheles from the species A. strodei, A. albitarsis, A. fluminensis, A. evansae, A. nuneztovari, A. nyssorhynchela lutzi and A. oswaldoi collected at the departments of Caaguazú and Alto Paraná in Paraguay. For the amplification and sequentiation, primers reported for the VGSC gen of A. strodei in Guatemala were used and were specific only for A. strode in this case. The sequence revealed the TTA codon that codifies for a leucine as the TTG sequence, reported for the susceptible version at position L1014. The amplified fragment is approximately 225 base pairs. To our knowledge, this is the first characterization of the VGSC gene in Anopheles mosquitoes in Paraguay and for the species A. strodei

Sensibilidad aumentada a lidocaína: estudio genético de un caso / Increased sensitivity to lidocaine: Genetic study of a case

Systemic toxicity by local anesthetics (LAs) is a severe and feared complication in anesthetic practice that generally results from the administration of an inappropriately high dose of LAs or an injection at an inappropriate place, either intravascular or a site with high absorption[1]. However, it is known that the susceptibility to these drugs may vary within the population, which may occur due to genetic changes in the LA binding site, located in the potential-dependent Na+ channels (Nav), thus increasing or decreasing its affinity and, therefore, its clinical consequences. We present a case of a 61 years-old female patient with a medical history of increased sensitivity to LAs. In this scenario, a genetic study was performed to exclude a Nav channel dysfunction.

La toxicidad sistémica por anestésicos locales (ALs) es una grave y temida complicación en la práctica anestésica que generalmente resulta de la administración de una dosis inapropiadamente alta de ALs o a una inyección en un lugar inadecuado, llámese intravascular o un sitio al alta absorción[1]. A pesar de lo anterior, es conocido que la susceptibilidad al efecto de estos fármacos puede variar dentro de la población, lo cual puede ocurrir debido a cambios genéticos en el sitio de unión de los AL, localizado en los canales de Na+ dependientes de potencial (Nav), incrementando o disminuyendo así su afinidad y, por ende, sus consecuencias clínicas. Presentamos el caso de una paciente de 61 años con historia de sensibilidad aumentada a Als. En este escenario, se le ofreció un estudio genético para excluir una disfunción específica a nivel de canal Nav

Effect of carbamazepine on tetrodotoxin-resistant Na⁺ channels in trigeminal ganglion neurons innervating to the dura

Migraine is a neurological disorder characterized by recurrent and disabling severe headaches. Although several anticonvulsant drugs that block voltage-dependent Na⁺ channels are widely used for migraine, far less is known about the therapeutic actions of carbamazepine on migraine. In the present study, therefore, we characterized the effects of carbamazepine on tetrodotoxin-resistant (TTX-R) Na⁺ channels in acutely isolated rat dural afferent neurons, which were identified by the fluorescent dye DiI. The TTX-R Na⁺ currents were measured in medium-sized DiIpositive neurons using the whole-cell patch clamp technique in the voltage-clamp mode. While carbamazepine had little effect on the peak amplitude of transient Na⁺ currents, it strongly inhibited steady-state currents of transient as well as persistent Na⁺ currents in a concentration-dependent manner. Carbamazepine had only minor effects on the voltage-activation relationship, the voltage-inactivation relationship, and the use-dependent inhibition of TTX-R Na⁺ channels. However, carbamazepine changed the inactivation kinetics of TTX-R Na⁺ channels, significantly accelerating the development of inactivation and delaying the recovery from inactivation. In the current-clamp mode, carbamazepine decreased the number of action potentials without changing the action potential threshold. Given that the sensitization of dural afferent neurons by inflammatory mediators triggers acute migraine headaches and that inflammatory mediators potentiate TTX-R Na⁺ currents, the present results suggest that carbamazepine may be useful for the treatment of migraine headaches.

Paroxysmal Ataxia and Dysarthria in a Patient with Demyelinating Disease

Paroxysmal dysarthria and ataxia is characterized by abrupt onset of dysarthria and ataxia of unilateral limbs for seconds. We present a 45-year-old female patient with paroxysmal symptoms of dysarthria, right-sided ataxia, and a persistent symptom of upbeating nystagmus. Her brain fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging indicated potential diagnosis of demyelinating disease. The paroxysmal and persistent symptoms have recovered after phenytoin administration. Sodium channel blocker may play a role in reducing the ephaptic transmission in a demyelinated or re-myelinated lesion.

Preemptive application of QX-314 attenuates trigeminal neuropathic mechanical allodynia in rats

The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia. Immediate double application of QX-314 produced a greater attenuation of mechanical allodynia than a single application of QX-314. Immediate double application of 2% QX-314 reduced the CCI-ION-induced upregulation of GFAP and p-p38 expression in the trigeminal ganglion. The upregulated p-p38 expression was co-localized with NeuN, a neuronal cell marker. We also investigated the role of voltage-gated sodium channels (Navs) in the antinociception produced by preemptive application of QX-314 through analysis of the changes in Nav expression in the trigeminal ganglion following CCI-ION. Preemptive application of QX-314 significantly reduced the upregulation of Nav1.3, 1.7, and 1.9 produced by CCI-ION. These results suggest that long-lasting blockade of the transmission of pain signaling inhibits the development of neuropathic pain through the regulation of Nav isoform expression in the trigeminal ganglion. Importantly, these results provide a potential preemptive therapeutic strategy for the treatment of neuropathic pain after nerve injury.

Efficacy of ranolazine in lowering HbA1c in patients with type 2 diabetes mellitus: A meta-analysis

@#<p style="text-align: justify;"><strong>INTRODUCTION:</strong> Cardiovascular diseases and diabetes mellitus (DM) are two disease entities that commonly coexist in a single patient. Ranolazine is an active piperazine derivative approved by FDA in 2006 as an anti-anginal medication. It was noted to have HbA1c lowering effects in the trials on angina. The proposed mechanism of action is the inhibition of glucagon secretion by blocking the Na v1.3 isoform of sodium channels in pancreatic alpha cells leading to glucagon- and glucose-lowering effects. HbA1c lowering to a target of 6.5% in type 2 diabetes patients has been shown to reduce risk of microvascular complications. The objective of this study is to determine the efficacy and safety of Ranolazine in HbA1c lowering as an add-on therapy to existing anti-diabetic regimen.</p><p style="text-align: justify;"><strong>METHODS:</strong> A comprehensive literature search in PubMed, The Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov website, Google Scholar databases and EMBASE databases were made using the search terms "Randomized controlled trial", "Ranolazine," "HbA1c," and "glycosylated hemoglobin", as well as various combinations of these, was done to identify randomized control trials. No restriction on language and time were done. The authors extracted data for characteristics, quality assessment and mean change in HbA1c after at least eight weeks of treatment with ranolazine. The program RevMan 5.3 was used to generate the statistical analysis of the data.</p><p style="text-align: justify;"><strong>RESULTS:</strong> Six RCTs were included to make up a total of 1,650 diabetic patients. Five studies had moderate risk of bias assessment while one had low risk of bias assessment and hence was not included in the analysis. The overall analysis showed an HbA1c reduction of 0.35% 0.68 to -0.03, p-value=0.03) however, the population was heterogenous (I2=100%). The heterogeneity was not eliminated by sensitivity analysis.</p><p style="text-align: justify;"><strong>DISCUSSION:</strong> The results showed a statistically significant lowering of HbA1c with ranolazine. However, the population was heterogenous. The sources of heterogeneity could be the (1) differences in the level of glycemic control among subjects as indicated by baseline HbA1c levels, (2) the current anti-diabetic regimen of the study patients, i.e. whether or not they are on insulin therapy, (3) the presence or absence of ischemic heart disease and (5) duration of ranolazine therapy, and (4) the presence or absence of chronic kidney disease. When the analysis excluded the population with combination insulin therapy and ranolazine, the effect becomes non-significant. Thus, the HbA1c lowering effect may have been from the insulin therapy rather than the ranolazine.</p><p style="text-align: justify;"><strong>CONCLUSION:</strong> Ranolazine as anti-diabetic therapy shows statistically significant HbA1c lowering effect. It can be a potential treatment option for patients with both DM and angina pectoris. However, well-designed, prospective trials are still recommended to determine the effect on a less heterogenous population. Likewise, more studies are needed to determine its safety.</p>

Efficacy of ranolazine in lowering HbA1c in patients with type 2 diabetes mellitus: A meta-analysis

INTRODUCTION: Cardiovascular diseases and diabetes mellitus (DM) are two disease entities that commonly coexist in a single patient. Ranolazine is an active piperazine derivative approved by FDA in 2006 as an anti-anginal medication. It was noted to have HbA1c lowering effects in the trials on angina. The proposed mechanism of action is the inhibition of glucagon secretion by blocking the Na v1.3 isoform of sodium channels in pancreatic alpha cells leading to glucagon- and glucose-lowering effects. HbA1c lowering to a target of 6.5% in type 2 diabetes patients has been shown to reduce risk of microvascular complications. The objective of this study is to determine the efficacy and safety of Ranolazine in HbA1c lowering as an add-on therapy to existing anti-diabetic regimen. METHODS: A comprehensive literature search in PubMed, The Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov website, Google Scholar databases and EMBASE databases were made using the search terms "Randomized controlled trial", "Ranolazine," "HbA1c," and "glycosylated hemoglobin", as well as various combinations of these, was done to identify randomized control trials. No restriction on language and time were done. The authors extracted data for characteristics, quality assessment and mean change in HbA1c after at least eight weeks of treatment with ranolazine. The program RevMan 5.3 was used to generate the statistical analysis of the data. RESULTS: Six RCTs were included to make up a total of 1,650 diabetic patients. Five studies had moderate risk of bias assessment while one had low risk of bias assessment and hence was not included in the analysis. The overall analysis showed an HbA1c reduction of 0.35% 0.68 to -0.03, p-value=0.03) however, the population was heterogenous (I2=100%). The heterogeneity was not eliminated by sensitivity analysis. DISCUSSION: The results showed a statistically significant lowering of HbA1c with ranolazine. However, the population was heterogenous. The sources of heterogeneity could be the (1) differences in the level of glycemic control among subjects as indicated by baseline HbA1c levels, (2) the current anti-diabetic regimen of the study patients, i.e. whether or not they are on insulin therapy, (3) the presence or absence of ischemic heart disease and (5) duration of ranolazine therapy, and (4) the presence or absence of chronic kidney disease. When the analysis excluded the population with combination insulin therapy and ranolazine, the effect becomes non-significant. Thus, the HbA1c lowering effect may have been from the insulin therapy rather than the ranolazine. CONCLUSION: Ranolazine as anti-diabetic therapy shows statistically significant HbA1c lowering effect. It can be a potential treatment option for patients with both DM and angina pectoris. However, well-designed, prospective trials are still recommended to determine the effect on a less heterogenous population. Likewise, more studies are needed to determine its safety.

Neuroprotective Effect of Lacosamide on Hypoxic-Ischemic Brain Injury in Neonatal Rats

BACKGROUND AND PURPOSE: Lacosamide (LCM) is an antiepileptic drug that enhances the slow inactivation of sodium channels and modulates collapsin response mediator protein-2. LCM was recently demonstrated to exert a neuroprotective effect in a murine model of traumatic brain injury and status epilepticus. Assuming the same underlying excitotoxicity-related brain injury mechanism, we hypothesized that LCM would have a neuroprotective effect in hypoxic-ischemic brain injury. METHODS: We divided rats into three groups at each testing session: pre- or postfed with LCM, fed with normal saline, and sham. A hypoxic-ischemic brain injury was induced by subjecting 7-day-old rats to right carotid artery coagulation followed by 2.5 h of exposure to 8% oxygen. The animals were killed on postnatal day 12 to evaluate the severity of brain damage. Open field testing was also performed between week 2 and week 6, and the Morris water maze test was performed in week 7 after hypoxia-ischemia. RESULTS: The incidence of liquefactive cerebral infarction was lower in rats prefed with LCM at 100 mg/kg/dose, with the mortality rate being higher at higher doses (200 and 300 mg/kg/dose). The infarct areas were smaller in LCM-prefed rats in several brain regions including the hemisphere, hippocampus, cortex, and striatum. Spatial learning and memory function were better in LCM-prefed rats (p<0.05). No effect was observed in postfed rats. CONCLUSIONS: This study suggests that LCM pretreatment exerts a neuroprotective effect on hypoxia-ischemia in neonatal rats. The obtained results suggest that LCM pretreatment could be used as an effective neuroprotective method for neonates under hypoxic-ischemic conditions including heart surgery.

Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach

BACKGROUND/AIMS: Gastric hypersensitivity contributes to abdominal pain in patients with functional dyspepsia. Recent studies showed that hormones induced by stress are correlated with visceral hypersensitivity. However, the precise mechanisms underlying gastric hypersensitivity remain largely unknown. The aim of the present study was designed to investigate the roles of corticosterone (CORT) on excitability of dorsal root ganglion (DRG) neurons innervating the stomach. METHODS: DRG neurons innervating the stomach were labeled by DiI injection into the stomach wall. Patch clamp recordings were employed to examine neural excitability and voltage-gated sodium channel currents. Electromyograph technique was used to determine the responses of neck muscles to gastric distension. RESULTS: Incubation of acutely isolated DRG neurons with CORT significantly depolarized action potential threshold and enhanced the number of action potentials induced by current stimulation of the neuron. Under voltage-clamp mode, incubation of CORT enhanced voltage-gated sodium current density of the recorded neurons. Pre-incubation of GF109203X, an inhibitor of protein kinase C, blocked the CORT-induced hyperexcitability and potentiation of sodium currents. However, pre-incubation of H-89, an inhibitor of protein kinase A, did not alter the sodium current density. More importantly, intraperitoneal injection of CORT produced gastric hypersensitivity of healthy rats, which was blocked by pre-administration of GF109203X but not H-89. CONCLUSIONS: Our data strongly suggest that CORT rapidly enhanced neuronal excitability and sodium channel functions, which is most likely mediated by protein kinase C but not protein kinase A signaling pathway in DRG neurons innervating the stomach, thus underlying the gastric hypersensitivity induced by CORT injection.

Cardiac sodium channel, its mutations and their spectrum of arrhythmia phenotypes

The mechanisms of cellular excitability and propagation of electrical signals in the cardiac muscle are very important functionally and pathologically. The heart is constituted by three types of muscle: atrial, ventricular, and specialized excitatory and conducting fibers. From a physiological and pathophysiological point of view, the conformational states of the sodium channel during heart function constitute a significant aspect for the diagnosis and treatment of heart diseases. Functional states of the sodium channel (closed, open, and inactivated) and their structure help to understand the cardiac regulation processes. There are areas in the cardiac muscle with anatomical and functional differentiation that present automatism, thus subjecting the rest of the fibers to their own rhythm. The rate of these (pacemaker) areas could be altered by modifications in ions, temperature and especially, the autonomic system. Excitability is a property of the myocardium to react when stimulated. Another electrical property is conductivity, which is characterized by a conduction and activation process, where the action potential, by the all-or-nothing law, travels throughout the heart. Heart relaxation also stands out as an active process, dependent on the energetic output and on specific ion and enzymatic actions, with the role of sodium channel being outstanding in the functional process. In the gene mutation aspects that encode the rapid sodium channel (SCN5A gene), this channel is responsible for several phenotypes, such as Brugada syndrome, idiopathic ventricular fibrillation, dilated cardiomyopathy, early repolarization syndrome, familial atrial fibrillation, variant 3 of long QT syndrome, multifocal ectopic ventricular contractions originating in Purkinje arborizations, progressive cardiac conduction defect (Lenègre disease), sudden infant death syndrome, sick sinus syndrome, sudden unexplained nocturnal death syndrome, among other sodium channel alterations with clinical overlapping. Finally, it seems appropriate to consider the "sodium channel syndrome" (mutations in the gene of the alpha subunit of the sodium channel, SCN5A gene) as a single clinical entity that may manifest in a wide range of phenotypes, to thus have a better insight on these cardiac syndromes and potential outcomes for their clinical treatment.

Os mecanismos da excitabilidade celular e de propagação dos sinais elétricos no músculo cardíaco são de grande importância funcional e patológica. O coração é composto por três tipos de músculo: atrial, ventricular e das fibras especializadas excitatórias e condutoras. Do ponto de vista fisiológico e fisiopatológico os estados conformacionais do canal de sódio constitui-se um importante aspecto para o diagnóstico e tratamento de doenças cardíacas. A descrição dos estados funcionais do canal de sódio (fechado, aberto e inativado) e sua estrutura ajudam a compreensão dos processos de regulação cardíaca. Há áreas no músculo cardíaco com diferenciação anatômica e funcional que possuem automatismo submetendo as demais fibras ao seu próprio ritmo. A frequência dessas áreas (marca-passo) pode ser alterada por modificações iônicas, pela temperatura e, especialmente, do sistema autonômico. Já a excitabilidade é a propriedade que tem o miocárdio de reagir quando estimulado. A outra propriedade elétrica é a condutibilidade, que se caracteriza por um processo de condução e ativação, no qual o potencial de ação, pela ei do tudo ou nada, percorre todo o coração. Destaca-se que o relaxamento do coração também é um processo ativo, dependente de gasto energético e de ações iônicas e enzimáticas específicas, destacando o papel dos canais de sódio no processo funcional. Nos aspectos das mutações no gene que codifica o canal rápido de sódio (gene SCN5A), este é responsável por vários fenótipos, tais como a síndrome de Brugada; a fibrilação ventricular idiopática, a miocardiopatia dilatada; a síndrome de repolarização precoce; a fibrilação atrial familiar; a síndrome do QT longo variante 3; as contrações ventriculares ectópicas multifocais originadas nas arborizações de Purkinje; o distúrbio progressivo de condução intraventricular cardíaco (doença de Lenègre); a síndrome da morte súbita do recém-nascido; a síndrome do nódulo sinusal doente; a síndrome da morte súbita noturna inesperada, entre outras alterações do canal de sódio com sobreposições clínicas, as chamadas "overpping". Por fim, parece ser apropriado considerar a "síndrome do canal de sódio" (mutações no gene da subunidade alfa do canal de sódio, gene SCN5A) como uma entidade clínica única que pode manifestar-se com um amplo espectro de fenótipos e assim, prover um melhor entendimento destas síndromes cardíacas e potencial desfecho para seu tratamento clínico.

Effects of Fluvastatin on Characteristics of Stellate Ganglion Neurons in a Rabbit Model of Myocardial Ischemia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Stellate ganglion (SG) plays an important role in cardiovascular diseases. The electrical activity of SG neurons is involved in the regulation of the autonomic nervous system. The aim of this research was to evaluate the effects of fluvastatin on the electrophysiological characteristics of SG neurons in a rabbit model of myocardial ischemia (MI).</p><p><b>METHODS</b>The MI model was induced by abdominal subcutaneous injections of isoproterenol in rabbits. Using whole-cell patch clamp technique, we studied the characteristic changes of ion channels and action potentials (APs) in isolated SG neurons in control group (n = 20), MI group (n = 20) and fluvastatin pretreated group (fluvastatin group, n = 20), respectively. The protein expression of sodium channel in SG was determined by immunohistochemical analysis.</p><p><b>RESULTS</b>MI and the intervention of fluvastatin did not have significantly influence on the characteristics of delayed rectifier potassium channel currents. The maximal peak current density of sodium channel currents in SG neurons along with the characteristics of activation curves, inactivation curves, and recovery curves after inactivation were changed in the MI group. The peak current densities of control group, MI group, and fluvastatin group (n = 10 in each group) were -71.77 ± 23.22 pA/pF, -126.75 ± 18.90 pA/pF, and -86.42 ± 28.30 pA/pF, respectively (F = 4.862, P = 0.008). Fluvastatin can decrease the current amplitude which has been increased by MI. Moreover, fluvastatin induced the inactivation curves and post-inactive recovery curves moving to the position of the control group. But the expression of sodium channel-associated protein (Nav1.7) had no significantly statistical difference among the three groups. The percentages of Nav1.7 protein in control group, MI group, and fluvastatin group (n = 5 in each group) were 21.49 ± 7.33%, 28.53 ± 8.26%, and 21.64 ± 2.78%, respectively (F = 1.495, P = 0.275). Moreover, MI reduced the electrical activity of AP and increased amplitude of AP, fluvastatin pretreatment could recover amplitude and electrical activity of AP. The probability of neurons induced continuous APs were 44.44%, 14.29%, and 28.57% in control group, MI group, and fluvastatin group, respectively.</p><p><b>CONCLUSIONS</b>Fluvastatin pretreatment can recover electrophysiology characteristics of ion channel and AP in SG neurons in a rabbit model of MI. It could be considered as potential method for treating coronary heart diseases.</p>

Effects of electroacupuncture at "Neiguan" (PC 6) on sodium channel-related proteins in rats with ischemic myocardial injury / 中国针灸

<p><b>OBJECTIVE</b>To explore the protective mechanism of electroacupuncture (EA) at "Neiguan" (PC 6) on ischemic myocardial injury, and to explain the response patterns and characteristics of the specific effect of acupoints along meridians in sodium channel in the level of cardiac organ.</p><p><b>METHODS</b>A total of 60 SPF male rats were randomly divided into a blank group, a model group, a non-acupoint group, a Neiguan group and a Lieque group, 12 cases in each one. Except the blank group, rats in the remaining group were treated with subcutaneous injection of isoprenaline to establish the model of myocardial ischemia. Rats in the Neiguan group, Lieque group and non- acupoint group were treated with EA, dilatational wave, with a frequency of 2 Hz/20 Hz. The intensity was 2-3 mA. The needles were retained for 20 min per time, once a day for consecutive 7 days. In the blank group and control group, the rats were grasped and fixed at the treating time each day. The western-blot method was used to test the expression of voltage-gated sodium channel alpha subunit (Nav 1.5), protein tyrosine kinase (PTKs) and protein tyrosine phosphatase (PTPs).</p><p><b>RESULTS</b>The expression of Nav 1.5 and PTKs in the model group was lower than that in the blank group (both P<0. 01); the expression in the Neiguan group and Lieque group was higher than that in the model group (all P < 0.01); the expression of Nav 1.5 and PTKs in the Neiguan group was higher than that in the Lieque group (both P < 0.01). The expression of PTPs in the model group and non-acupoint group was higher than that in the blank group (both P < 0.01); the expression of PTPs in the Neiguan group and Lieque group was significantly down-regulated, which was lower than the model group (both P < 0.01); the down-regulation in the Neiguan group was significantly different from that in the Lieque group (P < 0.05).</p><p><b>CONCLUSION</b>EA at "Neiguan" (PC 6), by down-regulating the expression of PTPs, up-regulating the expression of Nav 1.5 and PTKs, is likely to achieve the aim of regulation on sodium channel activity and calcium overload, further to improve myocardial ischemia, which provides experimental basis for the theory of the specific effect of acupoints along meridians.</p>

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.

A Case of Aconite Poisoning Successfully Recovered after Intravenous Fat Emulsion Therapy

Aconitum is a genus of various species of flowering plants that belongs to the Family Ranunculaceae. Most Aconitum sp. have extremely toxic alkaloid substances such as aconitine, mesaconitine and hypaconitine. Among these substances, aconitine can cause fatal cardiotoxicity by activating sodium channels followed by calcium channels in myocardial cells. Even though there have been various therapeutic plans suggested comprising antidotes based on diverse case reports and studies, there is no confirmatory treatment protocol for aconite poisoning. Here, we report an aconite poisoning patient who had refractory ventricular tachyarrhythmia that did not respond to intravenous amiodarone therapies even though they were sustained for over 2 hours, but showed successful recovery following intravenous fat emulsions (IFE) therapy.

A Case of Aconite Poisoning Successfully Recovered after Intravenous Fat Emulsion Therapy

Aconitum is a genus of various species of flowering plants that belongs to the Family Ranunculaceae. Most Aconitum sp. have extremely toxic alkaloid substances such as aconitine, mesaconitine and hypaconitine. Among these substances, aconitine can cause fatal cardiotoxicity by activating sodium channels followed by calcium channels in myocardial cells. Even though there have been various therapeutic plans suggested comprising antidotes based on diverse case reports and studies, there is no confirmatory treatment protocol for aconite poisoning. Here, we report an aconite poisoning patient who had refractory ventricular tachyarrhythmia that did not respond to intravenous amiodarone therapies even though they were sustained for over 2 hours, but showed successful recovery following intravenous fat emulsions (IFE) therapy.

Flecainide-Induced Torsade de Pointes Successfully Treated with Intensive Pharmacological Therapy

Flecainide acetate is a potent class IC anti-arrhythmic drug with a major sodium channel blocking effect. Flecainide toxicity can cause myocardial impairment and precipitate circulatory collapse. It may also result in life-threatening arrhythmia, although cases of flecainide-induced torsades de pointes are rare. Furthermore, the electrical and hemodynamic deteriorations observed during flecainide toxicity may not respond to conventional treatments. In the present study, we report the case of a 20-year-old Korean man with flecainide poisoning, who presented with hypotension. The patient was successfully treated with sodium bicarbonate, amiodarone, MgSO₄, and lidocaine, with no recourse to extracorporeal therapy. Although there is no standard therapy for flecainide toxicity, this report demonstrates that intensive pharmacological treatment is beneficial in cases of flecainide overdose.

Pneumococcal meningitis: epidemiological profile pre- and post-introduction of the pneumococcal 10-valent conjugate vaccine / Meningite pneumocócica: perfil epidemiológico pré e pós a introdução da vacina pneumocócica conjugada 10valente

OBJECTIVES: To evaluate the possible effects of the introduction of the pneumococcal conjugate 10-valent vaccine schedule in the state of Parana on pneumococcal meningitis cases and to assess the distribution of serotypes among cases. METHOD: Cross-sectional study with retrospective data collection of cases of pneumococcal meningitis in the state of Paraná reported to Sistema de Informação de Agravos de Notificação (SINAN), from 1998 to 2011. A total of 1,339 cases of pneumococcal meningitis were analyzed; 1,205 cases from the pre-vaccine period (1998-2009) were compared to 134 cases from the post-vaccine period (2010-2011). Descriptive and comparative statistical analyses (chi-squared test and prevalence ratio) were performed using JMP 5.1.2 statistical software (JMP Statistical Discovery, North Carolina, USA) and EPI INFO 6 (Centers for Disease Control and Prevention, Georgia, EUA). RESULTS: There was a significant reduction in the mean rates of incidence and mortality in the general population. The analysis of cases in the pre- and post-vaccination periods in the age groups covered by vaccination (younger than 2 years) showed significant reductions in incidence rates (6.01 cases/100,000 to 2.49 cases/100,000 individuals) and mortality (1.85 cases/100,000 population to 0.47 cases/100,000 population), while the mean lethality rate did not change significantly. There was a significant reduction in cases whose serotypes are included in the vaccine (80.7% to 53.3%). CONCLUSION: Even after a short time of use, the 10-valent pneumococcal conjugate vaccine has already had a significant impact in reducing the incidence and mortality of meningitis cases among infants, as well as the reduction of cases whose serotypes are included in the vaccine. .

OBJETIVOS: Avaliar os possíveis efeitos da introdução da vacina pneumocócica conjugada 10 valente no calendário vacinal no Paraná sobre os casos de meningite pneumocócica; avaliar a distribuição dos sorotipos dentre os casos. MÉTODO: Estudo observacional, transversal, com coleta de dados retrospectiva dos casos de meningite pneumocócica no Estado do Paraná, notificados ao SINAN, no período de 1998 a 2011. Foram analisados 1339 casos de meningite pneumocócica e comparados os 1205 casos do período pré-vacina (1998 a 2009) com os 134 do período pós-vacina (2010 a 2011). A análise estatística descritiva e comparativa (teste qui-quadrado e razão de prevalência) foi realizada no software de estatística JMP 5.1.2 (JMP Statistical Discovery, Carolina do Norte, EUA) e no Programa EPI INFO 6. RESULTADOS: Observou-se redução significativa das taxas médias de incidência e mortalidade na população geral. A análise dos casos nos períodos pré e pós-vacina nas faixas etárias contempladas pela vacinação (menores de 2 anos) mostrou reduções significativas das taxas de incidência (6,01 casos/100.000 para 2,49 casos/100.000 habitantes), mortalidade (1,85 casos/100.000 habitantes para 0,47 casos/100.000 habitantes), enquanto que a letalidade média não apresentou variação significativa. Houve redução significativa dos casos cujos sorotipos estão incluídos na vacina (80,7% para 53,3%). CONCLUSÃO: Mesmo com um tempo reduzido de uso, a vacina pneumocócica conjugada 10 valente já apresentou um impacto relevante na diminuição dos coeficientes de incidência e mortalidade dos casos de meningite entre os lactentes, além de redução de casos cujos sorotipos estão incluídos na vacina. .

Expressão dos genes codificadores de canais de sódio Nav 1.7, Nav 1.8 e Nav 1.9 em portadores da Síndrome de Ardência Bucal / Expression of coding genes sodium channel Nav 1.7, Nav 1.8 and Nav 1.9 in patients with Burning Mouth Syndrome

A síndrome de ardência bucal (SAB) é uma condição caracterizada pelo sintoma de ardência na mucosa oral, na ausência de qualquer sinal clínico. Sua etiologia é desconhecida e, até o momento, não dispõe de tratamento efetivo. Há entretanto características de doença neuropática que justificam investigações nesse sentido. O objetivo desse estudo foi mensurar a expressão gênica dos receptores de canais de sódio, Nav 1.7, Nav 1.8 e Nav 1.9, nos pacientes portadores de SAB. A casuística foi composta por dois grupos sendo o grupo de estudo composto por 12 pacientes portadores de SAB, selecionados através do critério estabelecido pela International Headache Society, em 2013 e o grupo controle composto por 4 pacientes não portadores de SAB. As amostras analisadas foram coletadas do dorso lingual, por meio de biópsia realizada com punch de 3 mm e profundidade de 3 mm, estas foram submetidas ao método de análise RT-PCR em tempo real. A expressividade dos genes de canais de sódio foi avaliada nos indivíduos portadores de SAB em relação aos do grupo controle, sendo esta calculada a partir da normalização dos dados da quantificação destes com os da expressão do gene constitutivo (GAPDH), pelo método de Cicle Threshold comparativo e analisados estatisticamente por meio do teste estatístico Mann-Whitnney. Observou-se o aumento da expressão gênica do Nav 1.7 (fold-change = 38.70) e diminuição da expressão gênica do Nav 1.9 (fold-change = 0.89), porém sem diferenças estatisticamente significativas entre os grupos analisados. O gene Nav 1.8 não foi expresso em nenhuma das amostras analisadas. O Nav 1.7 expressa-se tanto em neurônios nociceptivos quanto no sistema nervoso autônomo e mutações no Nav 1.9 tem sido associada a perda de percepção dolorosa. Os resultados obtidos embora não estatisticamente significativos são compatíveis com as características da doença, justificando a extensão dos estudos na linha expressão de genes codificadores dos canais de sódio em pacientes com SAB.

Burning mouth syndrome (BMS) is a condition characterized by symptoms of burning in the oral mucosa, in the absence of any clinical signs. Its etiology is unknown and so far, it has no effective treatment. It is important to mention that BMS exhibits some traits of a neuropathic disease, what justifies a thorough investigation of this subject.The objective of this study was to measure the gene expression of the sodium channel receptors, Nav 1.7, Nav 1.8 and Nav 1.9, in patients with BMS.The sample was composed of two groups, being the study group formed by 12 patients with SAB, selected according to the criteria established by the International Headache Society in 2013, while the compound control group had 4 patients without SAB. The analyzed samples were collected from the tongue, by the biopsy technique with a 3 mm punch and 3mm depth. These samples were processed in real time, following the guidelines set forth by the RT-PCR method. The expressiveness of the sodium channels was evaluated in the individuals with BMS in relation to control group, which was calculated from the normalization of these data with the quantification of the expression of a constitutive gene (GAPDH) by the Cycle Threshold comparative methods and statistically compared by Man-Whitnney test. We observed an increased gene expression of Nav 1.7 (fold-change = 38.70) and a decreased gene expression of Nav 1.9 (fold-change = 0.89), but no statistically significant differences between the groups. Nav 1.8 gene was not expressed in any of the samples. Nav 1.7 is expressed in both nociceptive neurons as the autonomic nervous system and changes in Nav 1.9 has been associated with loss of pain perception. The results although not statistically significant are consistent with the disease characteristics, justifying the extension line of the studies on the expression of genes encoding the sodium channel in patients with SAB.