Treatment and diagnosis of chemotherapy-induced peripheral neuropathy: An update.

When peripheral neuropathy occurs due to chemotherapy treatment, it is referred to as chemotherapy-induced peripheral neuropathy (CIPN). Typically, symptoms are sensory rather than motor and include reduced feeling and heightened sensitivity to pressure, pain, temperature, and touch. The pathophysiology of CIPN is very complex, and it involves multiple mechanisms leading to its development which will be described specifically for each chemotherapeutic class. There are currently no approved or effective agents for CIPN prevention, and Duloxetine is the only medication that is an effective treatment against CIPN. There is an unavoidable necessity to develop preventative and treatment approaches for CIPN due to its detrimental impact on patients' lives. The purpose of this review is to examine CIPN, innovative pharmacological and nonpharmacological therapy and preventive strategies for this illness, and future perspectives for this condition and its therapies.

Allium macrostemon Bunge. exerts analgesic activity by inhibiting NaV1.7 channel.

ETHNOPHARMACOLOGICAL RELEVANCE: Allium macrostemon Bunge. is an edible Chinese herb traditionally used for the treatment of thoracic pain, stenocardia, heart asthma and diarrhea. Although its biological potential has been extensively proven such as antioxidant activity, antiplatelet aggregation, vasodilation and antidepressant-like activity, there are no reports in the literature regarding its pharmacological analgesic activity. AIM OF THE STUDY: The study was carried out to examine the anti-nociceptive activity of the crude extract of A. macrostemon bulbs and interpret its likely molecular target. MATERIALS AND METHODS: The bulbs of A. macrostemon were gathered, dried-up, and extracted with water (AMWD). AMWD was subjected to activity testing, using chemical-induced (acetic acid and formalin test) and heat-induced (hot plate) pain models. To evaluate the likely mechanistic strategy involved in the analgesic effect of AMWD, whole-cell patch clamp recordings were conducted in acutely dissociated dorsal root ganglion (DRG) neurons and human embryonic kidney 293T (HEK293T) cells expressing pain-related receptors. Electrophysiological methods were employed to detect the action potentials of DRG neurons and potential targets of A. macrostemon. RESULTS: AMWD showed significant palliative effect in all heat and chemical induced pain assays. Moreover, AMWD significantly reduces the excitability of dorsal root ganglion neurons by reducing the firing frequency of action potentials. Further analysis revealed that voltage-gated sodium channel Nav1.7 is the potential target of A. macrostemon for its analgesic activity. CONCLUSION: This study has brought new scientific evidence of preclinical efficacy of A. macrostemon as an anti-nociceptive agent. Apparently, these effects are involved with the inhibition of the voltage-sensitive Nav1.7 channel contributing to the reduction of peripheral neuronal excitability. Our present study justifies the folkloric usage of A. macrostemon as a remedy for several pain states. Furthermore, A. macrostemon is a good resource for the development of analgesic drugs targeting Nav1.7 channel.

Analgesic effect of the main components of Corydalis yanhusuo (yanhusuo in Chinese) is caused by inhibition of voltage gated sodium channels.

ETHNOPHARMACOLOGY RELEVANCE: Pain often causes a series of abnormal changes in physiology and psychology, which can lead to disease and even death. Drug therapy is the most basic and commonly used method for pain relief and management. Interestingly, at present, hundreds of traditional Chinese medicines have been reported to be used for pain relief, most of which are monomer preparations, which have been developed into new painkillers. Corydalis yanhusuo is a representative of one of these medicines and is available for pain relief. AIM OF THE STUDY: This study aims to determine the analgesic effect and the potential targets of the monomers derived from Corydalis yanhusuo, and to explore any possible associated cardiac risk factors. MATERIALS AND METHODS: In this study, four monomers derived from Corydalis yanhusuo (tetrahydropalmatine, corydaline, protopine, dehydrocorydaline) were tested in vivo, using the formalin-induced pain model to determine their analgesic properties. Their potential targets were also determined using whole cell patch clamp recordings and myocardial enzyme assays. RESULTS: The results showed that all monomers showed analgesic activity and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.7, which indicating that Nav1.7 might be involved in the analgesic mechanism of Corydalis yanhusuo. Protopine increased the level of creatine kinase-MB (CK-MB) and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.5, indicating that Nav1.5 might be involved in the cardiac risk associated with protopine treatment. CONCLUSION: These data showed that tetrahydropalmatine produced the best analgesic effect and the lowest cardiac risk. Thus, voltage gated sodium channels (VGSCs) might be the main targets associated with Corydalis yanhusuo. This study, therefore, provides valuable information for future studies and use of traditional Chines medicines for the alleviation of pain.

Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice.

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aß- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

Neoline, an active ingredient of the processed aconite root in Goshajinkigan formulation, targets Nav1.7 to ameliorate mechanical hyperalgesia in diabetic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Goshajinkigan (GJG), a traditional Japanese Kampo formula, has been shown to exhibit several pharmacological actions, including antinociceptive effects. Processed aconite root (PA), which is considered to be an active ingredient of GJG, has also been demonstrated to have an ameliorative effect on pain, such as diabetic peripheral neuropathic pain. We recently identified neoline as the active ingredient of both GJG and PA that is responsible for its effects against oxaliplatin-induced neuropathic pain in mice. AIM OF THE STUDY: In the present study, we investigated whether GJG, PA, and neoline could inhibit Nav1.7 voltage-gated sodium channel (VGSC) current and whether neoline could ameliorate mechanical hyperalgesia in diabetic mice. MATERIALS AND METHODS: To assess the electrophysiological properties of GJG extract formulation, powdered PA, and neoline on Nav1.7 VGSCs, whole-cell patch clamp recording was performed using human HEK293 cells expressing Nav1.7 VGSCs. In addition, the ameliorative effects of neoline on diabetic peripheral neuropathic pain were evaluated using the von Frey test in streptozotocin (STZ)-induced diabetic model mice. RESULTS: GJG extract formulation significantly inhibited Nav1.7 VGSC peak current. Powdered PA also inhibited Nav1.7 VGSC peak current. Like GJG and PA, neoline could inhibit Nav1.7 VGSC current. When diabetic mice were treated with neoline by intraperitoneal acute administration, the mechanical threshold was increased in diabetic mice, but not in non-diabetic mice, in a behavioral study. CONCLUSION: These results suggest that neoline might be a novel active ingredient of GJG and PA that is one of responsible ingredients for ameliorating mechanical hyperalgesia in diabetes via the inhibition of Nav1.7 VGSC current at least.

High-throughput screening against protein:protein interaction interfaces reveals anti-cancer therapeutics as potent modulators of the voltage-gated Na+ channel complex.

Multiple voltage-gated Na+ (Nav) channelopathies can be ascribed to subtle changes in the Nav macromolecular complex. Fibroblast growth factor 14 (FGF14) is a functionally relevant component of the Nav1.6 channel complex, a causative link to spinocerebellar ataxia 27 (SCA27) and an emerging risk factor for neuropsychiatric disorders. Yet, how this protein:channel complex is regulated in the cell is still poorly understood. To search for key cellular pathways upstream of the FGF14:Nav1.6 complex, we have developed, miniaturized and optimized an in-cell assay in 384-well plates by stably reconstituting the FGF14:Nav1.6 complex using the split-luciferase complementation assay. We then conducted a high-throughput screening (HTS) of 267 FDA-approved compounds targeting known mediators of cellular signaling. Of the 65 hits initially detected, 24 were excluded based on counter-screening and cellular toxicity. Based on target analysis, potency and dose-response relationships, 5 compounds were subsequently repurchased for validation and confirmed as hits. Among those, the tyrosine kinase inhibitor lestaurtinib was highest ranked, exhibiting submicromolar inhibition of FGF14:Nav1.6 assembly. While providing evidence for a robust in-cell HTS platform that can be adapted to search for any channelopathy-associated regulatory proteins, these results lay the potential groundwork for repurposing cancer drugs for neuropsychopharmacology.

Use of Cryopreserved Hepatocytes as Part of an Integrated Strategy to Characterize In Vivo Clearance for Peptide-Antibody Conjugate Inhibitors of Nav1.7 in Preclinical Species.

The identification of nonopioid alternatives to treat chronic pain has received a great deal of interest in recent years. Recently, the engineering of a series of Nav1.7 inhibitory peptide-antibody conjugates has been reported, and herein, the preclinical efforts to identify novel approaches to characterize the pharmacokinetic properties of the peptide conjugates are described. A cryopreserved plated mouse hepatocyte assay was designed to measure the depletion of the peptide-antibody conjugates from the media, with a correlation being observed between percentage remaining in the media and in vivo clearance (Pearson r = -0.5525). Physicochemical (charge and hydrophobicity), receptor-binding [neonatal Fc receptor (FcRn)], and in vivo pharmacokinetic data were generated and compared with the results from our in vitro hepatocyte assay, which was hypothesized to encompass all of the aforementioned properties. Correlations were observed among hydrophobicity; FcRn binding; depletion rates from the hepatocyte assay; and ultimately, in vivo clearance. Subsequent studies identified potential roles for the low-density lipoprotein and mannose/galactose receptors in the association of the Nav1.7 peptide conjugates with mouse hepatocytes, although in vivo studies suggested that FcRn was still the primary receptor involved in determining the pharmacokinetics of the peptide conjugates. Ultimately, the use of the cryopreserved hepatocyte assay along with FcRn binding and hydrophobic interaction chromatography provided an efficient and integrated approach to rapidly triage molecules for advancement while reducing the number of in vivo pharmacokinetic studies. SIGNIFICANCE STATEMENT: Although multiple in vitro and in silico tools are available in small-molecule drug discovery, pharmacokinetic characterization of protein therapeutics is still highly dependent upon the use of in vivo studies in preclinical species. The current work demonstrates the combined use of cryopreserved hepatocytes, hydrophobic interaction chromatography, and neonatal Fc receptor binding to characterize a series of Nav1.7 peptide-antibody conjugates prior to conducting in vivo studies, thus providing a means to rapidly evaluate novel protein therapeutic platforms while concomitantly reducing the number of in vivo studies conducted in preclinical species.

3'-Methoxydaidzein exerts analgesic activity by inhibiting voltage-gated sodium channels.

Isoflavones are widely consumed by people around the world in the form of soy products, dietary supplements and drugs. Many isoflavones or related crude extracts have been reported to exert pain-relief activities, but the mechanism remains unclear. Voltage-gated sodium channels (VGSCs) play important roles in excitability of pain sensing neurons and many of them are important nociceptors. Here, we report that several isoflavones including 3'-methoxydaidzein (3MOD), genistein (GEN) and daidzein (DAI) show abilities to block VGSCs and thus to attenuate chemicals and heat induced acute pain or chronic constriction injury (CCI) induced pain hypersensitivity in mice. Especially, 3MOD shows strong analgesic potential without inducing addiction through inhibiting subtypes NaV1.7, NaV1.8 and NaV1.3 with the IC50 of 181 ± 14, 397 ± 26, and 505 ± 46 nmol·L-1, respectively, providing a promising compound or parent structure for the treatment of pain pathologies. This study reveals a pain-alleviating mechanism of dietary isoflavones and may provide a convenient avenue to alleviate pain.

Neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype: A back-translational study of oxcarbazepine.

BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, oxcarbazepine markedly inhibited punctate mechanical-, dynamic brush- and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic oxcarbazepine, supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. SIGNIFICANCE: The inhibitory effects of lidocaine and oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism-based rationale for bench-to-bedside translation when screening novel drugs.

Discovery of Indole- and Indazole-acylsulfonamides as Potent and Selective NaV1.7 Inhibitors for the Treatment of Pain.

3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.

3'-Methoxydaidzein exerts analgesic activity by inhibiting voltage-gated sodium channels / 中国天然药物

Isoflavones are widely consumed by people around the world in the form of soy products, dietary supplements and drugs. Many isoflavones or related crude extracts have been reported to exert pain-relief activities, but the mechanism remains unclear. Voltage-gated sodium channels (VGSCs) play important roles in excitability of pain sensing neurons and many of them are important nociceptors. Here, we report that several isoflavones including 3'-methoxydaidzein (3MOD), genistein (GEN) and daidzein (DAI) show abilities to block VGSCs and thus to attenuate chemicals and heat induced acute pain or chronic constriction injury (CCI) induced pain hypersensitivity in mice. Especially, 3MOD shows strong analgesic potential without inducing addiction through inhibiting subtypes Na1.7, Na1.8 and Na1.3 with the IC of 181 ± 14, 397 ± 26, and 505 ± 46 nmol·L, respectively, providing a promising compound or parent structure for the treatment of pain pathologies. This study reveals a pain-alleviating mechanism of dietary isoflavones and may provide a convenient avenue to alleviate pain.

NaV1.1 inhibition can reduce visceral hypersensitivity.

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Probing flecainide block of INa using human pluripotent stem cell-derived ventricular cardiomyocytes adapted to automated patch-clamping and 2D monolayers.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are emerging tools for applications such as drug discovery and screening for pro-arrhythmogenicity and cardiotoxicity as leading causes for drug attrition. Understanding the electrophysiology (EP) of hPSC-CMs is essential but conventional manual patch-clamping is highly laborious and low-throughput. Here we adapted hPSC-CMs derived from two human embryonic stem cell (hESC) lines, HES2 and H7, for a 16-channel automated planar-recording approach for single-cell EP characterization. Automated current- and voltage-clamping, with an overall success rate of 55.0 ±â€¯11.3%, indicated that 90% of hPSC-CMs displayed ventricular-like action potential (AP) and the ventricular cardiomyocytes (VCMs) derived from the two hESC lines expressed similar levels of INa, ICaL, Ikr and If and similarly lacked Ito and IK1. These well-characterized hPSC-VCMs could also be readily adapted for automated assays of pro-arrhythmic drug screening. As an example, we showed that flecainide (FLE) induced INa blockade, leftward steady-state inactivation shift, slowed recovery from inactivation in our hPSC-VCMs. Since single-cell EP assay is insufficient to predict drug-induced reentrant arrhythmias, hPSC-VCMs were further reassembled into 2D human ventricular cardiac monolayers (hvCMLs) for multi-cellular electrophysiological assessments. Indeed, FLE significantly slowed the conduction velocity while causing AP prolongation. Our RNA-seq data suggested that cell-cell interaction enhanced the maturity of hPSC-VCMs. Taken collectively, a combinatorial approach using single-cell EP and hvCMLs is needed to comprehensively assess drug-induced arrhythmogenicity.

Vitex negundo induces an anticonvulsant effect by inhibiting voltage gated sodium channels in murine Neuro 2A cell line.

Vitex negundo (Vn) extract is famous for the treatment of neurological diseases such as migraine and epilepsy. These neurological diseases have been associated with abnormally increased influx of sodium ions into the neurons. Drugs that inhibit voltage gated sodium channels can be used as potent anti-epileptics. Till now, the effects of Vn on sodium channels have not been investigated. Therefore, we have investigated the effects of methalonic fraction of Vn extract in Murine Neuro 2A cell line. Cells were cultured in a defined medium with or without the Vn extract (100 µg/ml). Sodium currents were recorded using whole-cell patch clamp method. The data show that methanolic extract of Vn inhibited sodium currents in a dose dependent manner (IC50 =161µg/ml). Vn (100 µg/ml) shifted the steady-state inactivation curve to the left or towards the hyper polarization state. However, Vn did not show any effects on outward rectifying potassium currents. Moreover, Vn (100 µg/ml) significantly reduced the sustained repetitive (48±4.8%, P<0.01) firing from neonatal hippocampal neurons at 12 DIV. Hence, our data suggested that inhibition of sodium channels by Vn may exert pharmacological effects in reducing pain and convulsions.

The effect of ethanol extract of Glycyrrhiza uralensis on the voltage-gated sodium channel subtype 1.4.

To investigate the inhibitory effect of Glycyrrhiza uralensis (G. uralensis) and its monomeric compounds on Nav1.4 voltage-gated sodium channels (VGSCs) and analyze the relationship between the content of its marker compounds and the inhibitory rate. Based on this study, we found that 4 mg/ml ethanol extract of G. uralensis at 30%, 50%, 70% and 90% (v/v) exhibited 77.00 ± 0.03%, 34.75 ± 0.09%, 100.00 ± 0.01% and 2.00 ± 0.01% inhibitory rates on INav1.4 respectively, and 8 mg/ml ethanol extract of G. uralensis at 30%, 50%, 70% and 90% (v/v) exhibited 99.00 ± 0.01%, 97.10 ± 0.02%, 100.00 ± 0.01% and 17.00 ± 0.04% inhibitory rates on INav1.4 respectively. Isoliquiritigenin, echinatin, liquiritin and glycyrrhizic acid exhibited higher inhibitory rates of 39.98 ± 4.55%, 33.20 ± 1.61%, 22.62 ± 0.30% and 20.54 ± 4.82% respectively. However, liquiritigenin, formononetin, neoisoliquiritin and glycyrrhetinic acid exhibited lower inhibitory rates of less than 20%. Further, liquiritin apioside, isoliquiritin and neoliquiritin exhibited almost no effect on INav1.4. These findings showed that glycyrrhizic acid reached a maximum concentration of 49.15 µg/ml, while echinatin had the lowest concentration. The ethanol extract of G. uralensis has significant inhibitory effects on Nav1.4 VGSCs. This may be an important mechanism in the treatment of gastrocnemius spasm and could guide further research regarding material basis and mechanism of the treatment of gastrocnemius spasm with peony and licorice decoction.

Cardiac sodium channel antagonism - Translation of preclinical in vitro assays to clinical QRS prolongation.

INTRODUCTION: Cardiac sodium channel antagonists have historically been used to treat cardiac arrhythmias by preventing the reentry of the electrical impulse that could occur following myocardial damage. However, clinical studies have highlighted a significant increase in mortality associated with such treatment. Cardiac sodium channel antagonist activity is now seen as an off-target pharmacology that should be mitigated during the drug development process. The aim of this study was to examine the correlation between in vitro/ex vivo assays that are routinely used to measure Nav1.5 activity and determine the translatability of the individual assays to QRS prolongation in the clinic. METHODS: A set of clinical compounds with known Nav1.5 activity was profiled in several in vitro/ex vivo assays (binding, membrane potential, patch clamp and the Langendorff isolated heart). Clinical data comprising compound exposure levels and changes in QRS interval were obtained from the literature. Sensitivity/specificity analysis was performed with respect to the clinical outcome. RESULTS: The in vitro assays showed utility in predicting QRS prolongation in the clinic. Optimal thresholds were defined for each assay (binding: IC20; membrane potential: IC10; patch clamp: IC20) and sensitivity (69-88%) and specificity (53-84%) values were shown to be similar between assay formats. DISCUSSION: The data provide clear statistical insight into the translatability of Nav1.5 antagonism data generated in vitro to potential clinical outcomes. These results improve our ability to understand the liability posed by such activity in novel development compounds at an early stage.

Cortical frequency-specific plasticity is independently induced by intracortical circuitry.

Auditory learning induces frequency-specific plasticity in the auditory cortex. Both the auditory cortex and thalamus are involved in the cortical plasticity; however, the precise role of the intracortical circuity remains unclear until the contributions of the thalamocortical inputs are controlled. Here, we induced cortical plasticity by local activation of the primary auditory cortex (AI) via intracortical electrical stimulation (ES) in C57 mice and found a similar pattern of cortical plasticity was induced by ESAI when the auditory thalamus was inactivated or remained active during the ESAI. The best frequencies (BFs) of the recorded cortical neurons shifted towards the BFs of the electrically stimulated ones. In addition, the BF shifts were linearly correlated to the BF differences between the recorded and stimulated cortical neurons. More importantly, the ratio of the linear function with thalamic inactivation was nearly the same as the ratio of the linear function in the control condition. Our data show that cortical frequency-specific plasticity was induced by ESAI with or without the thalamic inactivation; thus intracortical circuitry can be independently responsible for cortical frequency-specific plasticity.

Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia.

hNav1.7 receives a lot of attention owing to its attractive mechanism of action in pain processing pathway. We have previously reported our design of a novel series of tetrahydropyridine analogues towards hNav1.7 selective inhibitors. Herein, we disclose further efforts to the optimization of hit compound (-)-6, which led to the identification of aminocyclohexene analogues (-)-9 and (-)-17 with good potency, high selectivity, and minimal CYP inhibition. Both compounds (-)-9 and (-)-17 demonstrated improved pharmacokinetic profiles in rats, and robust efficacy in rat formalin-induced nociception and spinal nerve ligation (SNL) models.

Iritectol G, a novel iridal-type triterpenoid from Iris tectorum displays anti-epileptic activity in vitro through inhibition of sodium channels.

Iritectol G, a novel iridal-type triterpenoid containing an uncommon tetrahydrofuran moiety, was isolated from the rhizomes of Iris tectorum. The structure was elucidated by comprehensive spectroscopic analysis. Iritectol G inhibited spontaneous and 4-aminopyridine-evoked calcium oscillations in primary cultured neocortical neurons with IC50 values of 8.2µM and 12.5µM, respectively. Further electrophysiological study demonstrated that iritectol G preferred to interact with inactivated state of voltage-gated sodium channel with an IC50 value of 7.0µM. These data demonstrated that iritectol G was a novel sodium channel inhibitor.