Search Results (119)

Isoeugenol is a phenylpropanoid that is commonly found in essential oils and has been commonly used as a flavoring agent in the culinary field and an anesthetic in fish. Yet despite its similarity to well-known eugenol, there is a lack of data regarding how isoeugenol would directly modulate neuronal excitability to interfere with pain signaling. Here, we studied the effects of isoeugenol on voltage-activated Na⁺ currents (I_Na) as a means of starting to close the gap regarding the inhibitory properties of isoeugenol on neuronal excitability. We used rat dorsal root ganglia neurons under whole cell voltage clamp for the isolation of I_Na.. We show that isoeugenol effectively inhibits I_Na fully, reversibly, and in a dose-dependent manner. Our detailed analysis also indicates the direct interaction of isoeugenol with voltage-gated Na⁺ channels (VGSC) is likely state-dependent, as the inhibitory activity is enhanced by membrane depolarization. This effect is beneficial for pain management, as the drug would act more effectively as neuronal activity is promoted by membrane depolarization. Our data indicates a direct inhibition of VGSC by isoeugenol might constitute the main mechanism whereby this phenylpropanoid produces analgesia. This study serves as a basis for future approaches to deeply investigate the therapeutic potential of this drug or its derivatives. Full article

Cumulative inhibition of voltage-gated Na⁺ channel current (I_Na) caused by high-frequency depolarization plays a critical role in regulating electrical activity in excitable cells. As discussed in this review paper, exposure to certain small-molecule modulators can perturb I_Na during high-frequency stimulation, influencing the extent of cumulative inhibition and electrical excitability in excitable cells. Carbamazepine differentially suppressed transient or peak (I_Na(T)) and late (I_Na(L)) components of I_Na. Moreover, the cumulative inhibition of I_Na(T) during pulse-train stimulation at 40 Hz was enhanced by lacosamide. GV-58 was noted to exert stimulatory effect on I_Na(T) and I_Na(L). This stimulated I_Na was not countered by ω-conotoxin MVIID but was effectively reversed by ranolazine. GV-58′s exposure can slow down I_Na inactivation elicited during pulse-train stimulation. Lacosamide directly inhibited I_Na magnitude as well as promoted this cumulative inhibition of I_Na during pulse-train stimuli. Mirogabalin depressed I_Na magnitude as well as modulated frequency dependence of the current. Phenobarbital can directly modulate both the magnitude and frequency dependence of ionic currents, including I_Na. Previous investigations have shown that exposure to small-molecule modulators can perturb I_Na under conditions of high-frequency stimulation. This ionic mechanism plays a crucial role in modulating membrane excitability, hereby supporting the validity of these findings. Full article

Background: The development of cerebral organoids created from human pluripotent stem cells in 3D culture may greatly improve the discovery of neuropsychiatric medicines. Methods: In the current study we differentiated neural organoids from a human pluripotent stem cell line in vitro, recorded the development of neurophysiological activity using multielectrode arrays (MEAs) and characterized the neuropharmacology of synaptic signaling over 8 months in vitro. In addition, we investigated the ability of these organoids to display epileptiform activity in response to a convulsant agent and the effects of antiseizure medicines to inhibit this abnormal activity. Results: Single and bursts of action potentials from individual neurons and network bursts were recorded on the MEA plates and significantly increased and became more complex from week 7 to week 30, consistent with neural network formation. Neural spiking was reduced by the Na channel blocker tetrodotoxin but increased by the inhibitor of K_V7 potassium channels XE991, confirming the involvement of voltage-gated sodium and potassium channels in action potential activity. The GABA antagonists bicuculline and picrotoxin each increased the spike rate, consistent with inhibitory synaptic signaling. In contrast, the glutamate receptor antagonist kynurenic acid inhibited the spike rate, consistent with excitatory synaptic transmission in the organoids. The convulsant 4-aminopyridine increased spiking, bursts and synchronized firing, consistent with epileptiform activity in vitro. The anticonvulsants carbamazepine, ethosuximide and diazepam each inhibited this epileptiform neural activity. Conclusions: Together, our data demonstrate that neural organoids form inhibitory and excitatory synaptic circuits, generate epileptiform activity in response to a convulsant agent and detect the antiseizure properties of diverse antiepileptic drugs, supporting their value in drug discovery. Full article

Artificial photoelectric synapses exhibit great potential for overcoming the Von Neumann bottleneck in computational systems. All-inorganic halide perovskites hold considerable promise in photoelectric synapses due to their superior photon-harvesting efficiency. In this study, a novel wavy-structured CsPbBr₃/ZnO hybrid film was realized by depositing zinc oxide (ZnO) onto island-like CsPbBr₃ film via atomic layer deposition (ALD) at 70 °C. Due to the capability of ALD to grow high-quality films over small surface areas, dense and thin ZnO film filled the gaps between the island-shaped CsPbBr₃ grains, thereby enabling reduced light-absorption losses and efficient charge transport between the CsPbBr₃ light absorber and the ZnO electron-transport layer. This ZnO/island-like CsPbBr₃ hybrid synaptic transistor could operate at a drain-source voltage of 1.0 V and a gate-source voltage of 0 V triggered by green light (500 nm) pulses with low light intensities of 0.035 mW/cm². The device exhibited a quiescent current of ~0.5 nA. Notably, after patterning, it achieved a significantly reduced off-state current of 10⁻¹¹ A and decreased the quiescent current to 0.02 nA. In addition, this transistor was able to mimic fundamental synaptic behaviors, including excitatory postsynaptic currents (EPSCs), paired-pulse facilitation (PPF), short-term to long-term plasticity (STP to LTP) transitions, and learning-experience behaviors. This straightforward strategy demonstrates the possibility of utilizing neuromorphic synaptic device applications under low voltage and weak light conditions. Full article

The voltage-gated sodium channel Na_v1.7 is essential for pain perception and is an interesting target for the development of pain-relieving substances. Here, we investigated whether the Na_v1.7 channel is sensitive to harmaline, an alkaloid produced by the North African plant Peganum harmala. To this end, we used Chinese hamster ovary (CHO) cells expressing the human Na_v1.7 channel and studied Na⁺ channel pharmacology with an automated patch-clamp technique. Cells stimulated with depolarizing voltage pulses responded with typical transient inward currents. The Na⁺ channel blocker ranolazine inhibited whole-cell currents in a concentration-dependent manner (IC₅₀: 12.1 µM). Harmaline inhibited both peak and late Na⁺ currents. A complete block was achieved at 300 µM of harmaline, with half maximum inhibition occurring at 35.5 µM. In contrast to ranolazine, the effect of harmaline was voltage independent. Neither the current/voltage curves nor the steady-state inactivation curves were shifted in response to drug application (30 µM). We conclude that the plant alkaloid harmaline, which is used in traditional medicine in North Africa, is an effective blocker of the voltage-gated Na⁺ channel Na_v1.7. Our results offer a rationale for the use of harmaline against certain pain syndromes and rise hopes for the development of a new class of anti-nociceptive drugs targeting Na_v1.7. Full article

Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce the ion currents that are known to be functionally expressed in pituitary cells. These currents include a voltage-gated Na⁺ current (I_Na), erg-mediated K⁺ current (I_K(erg)), M-type K⁺ current (I_K(M)), hyperpolarization-activated cation current (I_h), and large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel. The biophysical characteristics of the respective ion current were described. Additionally, we also provide explanations for the effect of various drugs or compounds on each of these currents. GH₃-cell exposure to GV-58 can increase the magnitude of I_Na with a concurrent rise in the inactivation time constant of the current. The presence of esaxerenone, an antagonist of the aldosterone receptor, directly suppresses the magnitude of peak and late I_Na. Risperidone, an atypical antipsychotic agent, is effective at suppressing the I_K(erg) amplitude directly, and di(2-ethylhexyl)-phthalate suppressed I_K(erg). Solifenacin and kynurenic acid can interact with the K_M channel to stimulate I_K(M), while carisbamate and cannabidiol inhibit the I_h amplitude activated by sustained hyperpolarization. Moreover, the presence of either rufinamide or QO-40 can enhance the activity of single BK_Ca channels. To summarize, alterations in ion currents within native pituitary cells or pituitary tumor cells can influence their functional activity, particularly in processes like stimulus–secretion coupling. The effects of small-molecule modulators, as demonstrated here, bear significance in clinical, therapeutic, and toxicological contexts. Full article

Epilepsy is a neurological disorder characterized by repeated convulsions. Antiepileptic drugs (AEDs) are the main course of therapy for epilepsy. These medications are given according to each patient’s personal medical history and the types of seizures they suffer. They have been employed for decades to manage epilepsy, thus delivering relief from seizures through numerous mechanisms of action. Aside from their anticonvulsant attributes, current evidence suggests that certain AEDs may display potential inhibitory effects against cancer invasion and metastasis. This review explored the complicated interactions between the modes of action of AEDs and the pathways causing cancer, and the potential impact of AEDs on the invasion and metastasis of various forms of cancer, while addressing their associated side effects. For example, valproic acid inhibits histone deacetylase, causing hyperacetylation of genes, especially those regulating cell cycle, culminating in cell cycle arrest. Topiramate inhibits carbonic anhydrase, thus disrupting the acidic microenvironment needed for cancer cells to thrive. Lacosamide increases the slow inactivation of the voltage gated Na⁺ channel, thus inhibiting the growth, proliferation, and metastasis of many cancers. Although drug development is a complex task due to regulatory, intellectual property, and economic challenges, researchers are exploring drug repurposing tactics to overcome these challenges and to find new therapeutic alternatives for diseases like cancer. Thus, drug repurposing is considered among the most effective ways to develop drug candidates using novel properties and therapeutic characteristics, and this review also discusses these issues. Full article

Background: Pimozide is a conventional antipsychotic drug of the diphenylbutylpiperidine class, widely used for treating schizophrenia and delusional disorders and for managing motor and phonic tics in Tourette’s syndrome. Pimozide is known to block dopaminergic D2 receptors and various types of voltage-gated ion channels. Among its side effects, dizziness and imbalance are the most frequently observed, which may imply an effect of the drug on the vestibular sensory receptors, the hair cells. Amniotes possess two classes of vestibular hair cells, named type I and type II hair cells, which differ in terms of signal processing and transmission. We previously reported that Pimozide [3 μM] significantly increased a delayed outward rectifying K⁺ current (I_K,V). Methods and Results: In the present study, using the whole-cell patch-clamp technique we additionally show that Pimozide decreases the inward rectifying K⁺ current (I_K,1) and the mixed Na⁺/K⁺ current (I_h) of chicken embryo type II hair cells, whereas it does not affect type I hair cells’ ionic currents. Since ion channels’ expression can vary depending on age and animal species, in the present study, we also tested Pimozide in adult mouse vestibular hair cells. We found that, like in the chicken embryo, Pimozide significantly increases I_K,V and decreases I_K,1 and I_h in type II hair cells. However, in the adult mouse, Pimozide also slightly increased the outward rectifying K⁺ current in type I hair cells. Conclusions: While providing a possible explanation for the vestibular side effects of Pimozide in humans, its inhibitory action on mammalian hair cells might be of interest for the local treatment of vestibular disorders characterized by altered vestibular input, like Ménière’s disease. Full article

Tefluthrin (Tef) is categorized as a type-I pyrethroid insecticide, telmisartan (Tel) functions as an angiotensin II receptor blocker, and KB-R7943 has been identified as an inhibitor of the Na⁺-Ca²⁺ exchange process. However, the influence of these compounds on the amplitude and gating properties of voltage-gated Na⁺ current (I_Na) in neurons associated with pain signaling remains unclear. In cultured dorsal root ganglion (DRG) neurons, whole-cell current recordings revealed that Tef or Tel increased the peak amplitude of I_Na, concomitant with an elevation in the time constant of I_Na inactivation, particularly in the slow component. Conversely, exposure to KB-R7943 resulted in a depression in I_Na, coupled with a decrease in the slow component of the inactivation time constant of I_Na. Theoretical simulations and bifurcation analyses were performed on a modeled interneuron in the spinal dorsal horn. The occurrence of I_Na inactivation accentuated the subthreshold oscillations (SO) in the membrane potential. With an increase in applied current, SO became more pronounced, accompanied by the emergence of high-frequency spiking (HS) with a frequency of approximately 150 Hz. Moreover, an elevation in I_Na conductance further intensified both SO and HF. Consequently, through experimental and in silico studies, this work reflects that Tef, Tel, or KB-R7943 significantly impacts the magnitude and gating properties of I_Na in neurons associated with pain signaling. The alterations in I_Na magnitude and gating in these neurons suggest a close relationship with pain transmission. Full article

This study demonstrates a significant enhancement in the performance of thin-film transistors (TFTs) in terms of stability and mobility by combining indium–tungsten oxide (IWO) and zinc oxide (ZnO). IWO/ZnO heterojunction structures were fabricated with different channel thickness ratios and annealing environments. The IWO (5 nm)/ZnO (45 nm) TFT, annealed in O₂ ambient, exhibited a high mobility of 26.28 cm²/V·s and a maximum drain current of 1.54 μA at a drain voltage of 10 V, outperforming the single-channel ZnO TFT, with values of 3.8 cm²/V·s and 28.08 nA. This mobility enhancement is attributed to the formation of potential wells at the IWO/ZnO junction, resulting in charge accumulation and improved percolation conduction. The engineered heterojunction channel demonstrated superior stability under positive and negative gate bias stresses compared to the single ZnO channel. The analysis of O 1s spectra showed O_I, O_II, and O_III peaks, confirming the theoretical mechanism. A bias temperature stress test revealed superior charge-trapping time characteristics at temperatures of 25, 55, and 85 °C compared with the single ZnO channel. The proposed IWO/ZnO heterojunction channel overcomes the limitations of the single ZnO channel and presents an attractive approach for developing TFT-based devices having excellent stability and enhanced mobility. Full article

An accumulation of reactive oxygen species (ROS) in cardiomyocytes can induce pro-arrhythmogenic late Na⁺ currents by removing the inactivation of voltage-gated Na⁺ channels including the tetrodotoxin (TTX)-resistant cardiac α-subunit Nav1.5 as well as TTX-sensitive α-subunits like Nav1.2 and Nav1.3. Here, we explored oxidant-induced late Na⁺ currents in mouse cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in HEK 293 cells expressing Nav1.2, Nav1.3, or Nav1.5. Na⁺ currents in mouse cardiomyocytes and hiPSC-CMs treated with the oxidant chloramine T (ChT) developed a moderate reduction in peak current amplitudes accompanied by large late Na⁺ currents. While ChT induced a strong reduction in peak current amplitudes but only small persistent currents on Nav1.5, both Nav1.2 and Nav1.3 produced increased peak current amplitudes and large persistent currents following oxidation. TTX (300 nM) blocked ChT-induced late Na⁺ currents significantly stronger as compared to peak Na⁺ currents in both mouse cardiomyocytes and hiPSC-CMs. Similar differences between Nav1.2, Nav1.3, and Nav1.5 regarding ROS sensitivity were also evident when oxidation was induced with UVA-light (380 nm) or the cysteine-selective oxidant nitroxyl (HNO). To conclude, our data on TTX-sensitive Na⁺ channels expressed in cardiomyocytes may be relevant for the generation of late Na⁺ currents following oxidative stress. Full article

µ-Conotoxins are small, potent pore-blocker inhibitors of voltage-gated sodium (Na_V) channels, which have been identified as pharmacological probes and putative leads for analgesic development. A limiting factor in their therapeutic development has been their promiscuity for different Na_V channel subtypes, which can lead to undesirable side-effects. This review will focus on four areas of µ-conotoxin research: (1) mapping the interactions of µ-conotoxins with different Na_V channel subtypes, (2) µ-conotoxin structure–activity relationship studies, (3) observed species selectivity of µ-conotoxins and (4) the effects of µ-conotoxin disulfide connectivity on activity. Our aim is to provide a clear overview of the current status of µ-conotoxin research. Full article

Anethole is a phenolic compound synthesized by many aromatic plants. Anethole is a substance that humans can safely consume and has been studied for years as a biologically active molecule to treat a variety of conditions, including nerve damage, gastritis, inflammation, and nociception. Anethole is thought to carry out its biological activities through direct interaction with ion channels. Anethole is beneficial for neurodegenerative Alzheimer’s and Parkinson’s diseases. Nevertheless, nothing has been investigated regarding the effects of anethole on voltage-gated Na+ channels (VGSCs), which are major players in neuronal function. We used cultured dorsal root ganglion neurons from neonatal rats as a source of natively expressed VGSCs for electrophysiological studies using the whole-cell patch-clamp technique. Our data show that anethole interacts directly with VGSCs. Anethole quickly blocks and unblocks (when removed) voltage-activated Na+ currents in this preparation in a fully reversible manner. Anethole’s binding affinity to these channels increases when the inactive states of these channels are populated, similar to lidocaine’s effect on the same channels. Our data show that anethole inhibits neuronal activity by blocking VGSCs in a state-dependent manner. These findings relate to the putative anesthetic activity attributable to anethole, in addition to its potential benefit in neurodegenerative diseases. Full article

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH₃ cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K⁺ currents (I_K(M)), with an IC₅₀ of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of I_K(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The I_K(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K⁺ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na⁺ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (I_h) with an IC₅₀ of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of I_h was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on I_h elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in maintaining various physiological processes in the body, including blood pressure regulation, electrolyte balance, and overall cardiovascular health. However, any compounds or drugs known to perturb the RAAS might have an additional impact on transmembrane ionic currents. In this retrospective review article, we aimed to present a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS. It is noteworthy that these substances may also exhibit regulatory effects in different types of ionic currents. Apocynin, known to attenuate the angiotensin II-induced activation of epithelial Na⁺ channels, was shown to stimulate peak and late components of voltage-gated Na⁺ current (I_Na). Esaxerenone, an antagonist of the mineralocorticoid receptor, can exert an inhibitory effect on peak and late I_Na directly. Dexamethasone, a synthetic glucocorticoid, can directly enhance the open probability of large-conductance Ca²⁺-activated K⁺ channels. Sparsentan, a dual-acting antagonist of the angiotensin II receptor and endothelin type A receptors, was found to suppress the amplitude of peak and late I_Na effectively. However, telmisartan, a blocker of the angiotensin II receptor, was effective in stimulating the peak and late I_Na along with a slowing of the inactivation time course of the current. However, telmisartan’s presence can also suppress the erg-mediated K⁺ current. Moreover, tolvaptan, recognized as an aquaretic agent that can block the vasopressin receptor, was noted to suppress the amplitude of the delayed-rectifier K⁺ current and the M-type K⁺ current directly. The above results indicate that these substances not only have an interference effect on the RAAS but also exert regulatory effects on different types of ionic currents. Therefore, to determine their mechanisms of action, it is necessary to gain a deeper understanding. Full article