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Assessment of the effectiveness and safety of Ethosuximide in the Treatment of non-Diabetic Peripheral Neuropathic Pain: EDONOT-protocol of a randomised, parallel, controlled, double-blinded and multicentre clinical trial.

INTRODUCTION: Currently available analgesics are ineffective in 30-50% of patients suffering from neuropathic pain and often induce deleterious side effects. T-type calcium channel blockers (mibefradil, ethosuximide, NNC 55-0396) are of great interest for the development of new symptomatic treatments of neuropathic pain, due to their various effects on pain perception. Interestingly, ethosuximide, which has already been approved for treating epilepsy, is available on the European market for clinical use. Despite numerous preclinical data demonstrating an antinociceptive effect of ethosuximide …

Acquired cadmium resistance in metallothionein-I/II(-/-) knockout cells: role of the T-type calcium channel Cacnalpha1G in cadmium uptake.

Metallothioneins (MTs) are cytoplasmic proteins that sequester certain divalent cations and are considered a primary cellular defense agains … Zn(2+) (IC(50) = 7 microM), Mn(2+) (IC(50) = 0.4 microM), and the T-type Ca(2+) channel antagonist mibefradil (IC(50) = 5 microM), whereas other metals (including Fe(2+)) and L-type Ca(2+) channel antagonists had little effect. Immunoblot and real-time reverse transcription-polymerase chain reaction analysis indicated that the Cacnalpha(1G) T-type Ca(2+) ch …

T-type calcium channels drive the proliferation of androgen-receptor negative prostate cancer cells.

BACKGROUND: Androgen deprivation therapy (ADT) is the treatment of choice for metastatic prostate cancer (PCa). After an initial response to ADT, PCa cells can generate castration resistant (CRPC) or neuroendocrine (NEPC) malignancies, which are incurable. T-type calcium channels (TTCCs) are emerging as promising therapeutic targets for several cancers, but their role in PCa progression has never been investigated. METHODS: To examine the role of TTCCs in PCa, we analyzed their expression level, copy number variants (CNV) and prognostic significance using clinical datasets (Oncomine and cBioP

Development and regeneration of hair cells share common functional features.

The structural phenotype of neural connections in the auditory brainstem is sculpted by spontaneous and stimulus-induced neural activities during development. However, functional and molecular mechanisms of spontaneous action potentials (SAPs) in the developing cochlea are unknown. Additionally, it is unclear how regenerating hair cells establish their neural ranking in the constellation of neurons in the brainstem. We have demonstrated that a transient Ca(2+) current produced by the Ca(v)3.1 channel is expressed early in development to initiate spontaneous Ca(2+) spikes. Ca(v)1.3 currents, ty

NRF-2/HO-1 Pathway-Mediated SHOX2 Activation Is a Key Switch for Heart Rate Acceleration by Yixin-Fumai Granules.

Population aging has led to increased sick sinus syndrome (SSS) incidence; however, no effective and safe medical therapy has been reported … cium channel expression. In vitro experiment results indicated that ML385, si-SHOX2, LDN193189, and Mibefradil reversed YXFMs' effects. Moreover, we, for the first time, found that ROS accumulation may hinder SHOX2 expression; YXFMs can activate SHOX2 through the NRF-2/HO-1 pathway-mediated ROS scavenging and then regulate CACNA1G through the SHOX2/BMP4/GATA …

Histamine causes influx via T-type voltage-gated calcium channels in an enterochromaffin tumor cell line: potential therapeutic target in adverse food reactions.

The P-STS human ileal neuroendocrine tumor cells, as a model for gut enterochromaffin cells, are strongly and synergistically activated by histamine plus acetylcholine (ACh), presumably via histamine 4 receptors, and weakly activated by histamine alone. Sensing these signals, enterochromaffin cells could participate in intestinal intolerance or allergic reactions to food constituents associated with elevated histamine levels. In this study we aimed to analyze the underlying molecular mechanisms. Inhibition by mepyramine and mibefradil indicated that histamine alone caused a rise in intracellul…

Ca2+ and K+ channels of normal human adrenal zona fasciculata cells: properties and modulation by ACTH and AngII.

In whole cell patch clamp recordings, we found that normal human adrenal zona fasciculata (AZF) cells express voltage-gated, rapidly inactiv … K(+) current in human AZF cells at concentrations that stimulated cortisol secretion. Accordingly, mibefradil and CDC at concentrations that, respectively, blocked Cav3.2 and activated TREK-1, each inhibited both ACTH- and AngII-stimulated cortisol secretion. These results characterize the major Ca(2+) and K(+) channels expressed by normal human AZF cells a …

Follicle-stimulating hormone-induced Galphah/phospholipase C-delta1 signaling mediating a noncapacitative Ca2+ influx through T-type Ca2+ channels in rat sertoli cells.

Our previous study demonstrated that FSH-induced immediate Ca(2+) influx in rat Sertoli cells (SCs) is mediated by the Galphah/phospholipase … microM), a T-type calcium channel blocker, abolished the FSH-induced SC Ca(2+) influx. Furthermore, mibefradil (10 and 100 microm), another specific blocker for T-type Ca(2+) channels, dose-dependently suppressed the FSH-induced Ca(2+) influx. In contrast, nifedipine (10 and 50 microm) or omega-conotoxin GVIA (100 and 500 nm), blocker of L- or N-type Ca(2+) …

Heart rate as a risk factor for atherosclerosis and cardiovascular mortality: the effect of antihypertensive drugs.

The aim of this review is to highlight the importance of heart rate (HR) as a risk factor for cardiovascular disease, and to discuss the cla … his untoward effect, and seem to act also through inhibition of sympathetic discharge from the CNS. Mibefradil, a more recent calcium antagonist that selectively blocks voltage-dependent T-type calcium channels decreases HR without affecting left ventricular contractility. New drugs with agonistic properties at the I1-imidazoline receptors of the rostral ven …

Synthesis and biological evaluation of novel N3-substituted dihydropyrimidine derivatives as T-type calcium channel blockers and their efficacy as analgesics in mouse models of inflammatory pain.

Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellul … management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and T …

Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents.

We have used the whole cell patch-clamp method to study pharmacological properties of low-voltage-activated (LVA) Ca2+ current in freshly di … 303 microM, n = 2.3) > halothane (EC50 = 655 microM, n = 2.0) > ketamine (EC50 = 2.5 mM, n = 1.1). Mibefradil, a novel Ca2+ channel blocker, blocked dorsal root ganglion T current in a voltage- and use-dependent fashion with an EC50 of approximately 3 microM (n = 1.3). When compared with results on other T currents, these data indicate that significant diff …

T-type Ca²⁺ signalling downregulates MEK1/2 phosphorylation and cross-talk with the RAAS transcriptional response in cardiac myocytes.

Cardiac dysfunction is often associated with an increase in the activity of the renin-angiotensin II-aldosterone system (RAAS). Here, we highlight the cross-talk between the Ca(2+) signalling generated by cardiac T-type current (I(CaT)) and RAAS signalling. Neonatal rat cardiomyocytes exposed to aldosterone, angiotensin II or aldosterone plus angiotensin II co-treatment (AA) show an increase in I(CaT) density, with no cumulative effect of the AA co-treatment. AA increases the amount of T-type channel Ca(v)3.1 mRNA in a time-dependent manner. Angiotensin II increases Ca(v)3.1 mRNA stability, wh

Characterization of the commercially-available fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a marker for chloroquine resistance and uptake in a 96-well plate assay.

Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound l

Use of calcium channel blockers in hypertension.

During the past 20 years the number of subclasses of calcium channel blockers has increased from one to four. Three classes have only a single clinically approved compound: verapamil, diltiazem, and mibefradil. The fourth class, dihydropyridines, contains numerous compounds. All agents are effective in lowering blood pressure in short-term studies, and side effects that trouble the patient are infrequent. Long-term studies in hypertensive patients are limited. Short-acting agents such as nifedipine have been associated with an increased cardiovascular risk in some, but not all studies. These a…

T-Type Calcium Channels: A Mixed Blessing.

The role of T-type calcium channels is well established in excitable cells, where they preside over action potential generation, automaticity, and firing. They also contribute to intracellular calcium signaling, cell cycle progression, and cell fate; and, in this sense, they emerge as key regulators also in non-excitable cells. In particular, their expression may be considered a prognostic factor in cancer. Almost all cancer cells express T-type calcium channels to the point that it has been considered a pharmacological target; but, as the drugs used to reduce their expression are not complete

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… , G166NS, U3NNN-M NG108-15 and N1E-115 cell lines; primary glioblastoma cells (GBM-6, GBM-10) | N.A. | [ 25 , 125 ] Mibefradil | Esophageal carcinoma | KYSE150, KYSE180, TE1, TE8 | N.A. | [ 125 ] Mibefradil | Colon cancer | HCT116 | N.A. | [ 125 ] Mibefradil | Leukemia | MOLT-4, Jurkat, Ball, HL-60, … NB4, HEL, K-562, and U937 cell lines | N.A. | [ 125 ] Mibefradil | Glioma and glioblastome | Xenograft injection in mice | Not reported | [ 125 ] Mibefradil | Ovarian cancer | HO8910, A2780 cell lines | N.A. | [ 125 ] Mibefradil | Ovarian cancer | Xenograft nude mice | Not reported | [ 125 ] Mibefradil …

Development of a spontaneously active dorsal root ganglia assay using multiwell multielectrode arrays.

In vitro phenotypic assays of sensory neuron activity are important tools for identifying potential analgesic compounds. These assays are typically characterized by hyperexcitable and/or abnormally, spontaneously active cells. Whereas manual electrophysiology experiments provide high-resolution biophysical data to characterize both in vitro models and potential therapeutic modalities (e.g., action potential characteristics, the role of specific ion channels, and receptors), these techniques are hampered by their low throughput. We have established a spontaneously active dorsal root ganglia (DR

Integrative analysis of signaling and metabolic pathways, immune infiltration patterns, and machine learning-based diagnostic model construction in major depressive disorder.

Major depressive disorder (MDD) is a multifactorial disorder involving genetic and environmental factors, with unclear pathogenesis. This st … regulated pathways in the high-risk MDD group were identified, and multiple potential drugs such as Mibefradil, LY364947, ZLN005, STA- 5326, and vemurafenib were screened. Patients with MDD show differences in signaling pathways, metabolic pathways, and immune mechanisms. By constructing an MDD diagnostic model, we predicted the key genes of MDD and the char …

Prospects for repurposing CNS drugs for cancer treatment.

Drug repurposing is the idea of using an already approved drug for another disease or disorder away from its initial use. This new approach ensures the reduction in high cost required for developing a new drug in addition to the time consumed, especially in the tumor disorders that show an unceasing rising rate with an unmet success rate of new anticancer drugs. In our review, we will review the anti-cancer effect of some CNS drugs, including both therapeutic and preventive, by searching the literature for preclinical or clinical evidence for anticancer potential of central nervous system drug

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… This anti-angiogenic activity was due to the suppression of AKT phosphorylation and β- catenin pathway. 43 Pimozide Is another old D2 blocking agent used for Tourette’s Disorder. 44 Reviews from 2002 found a synergistic effect for both Pimozide and Mibefradil on T-type Ca+2 channels inhibition in which … Bertolesi GE The Ca2+ Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms . Mol Pharmacol 2002 ; 62 ( 2 ): 210 – 9 . 12130671 10.1124/mol.62.2.210 46. Mapes J Anandan L Li Q Neff A Clevenger C V. …

Cav3.1 (alpha1G) T-type Ca2+ channels mediate vaso-occlusion of sickled erythrocytes in lung microcirculation.

In the present study, we demonstrate that lung microvascular endothelial cells express a Cav3.1 (alpha1G) T-type voltage-gated Ca2+ channel, whereas lung macrovascular endothelial cells do not express voltage-gated Ca2+ channels. Voltage-dependent activation indicates that the Cav3.1 T-type Ca2+ current is shifted to a positive potential, at which maximum current activation is -10 mV; voltage-dependent conductance and inactivation properties suggest a "window current" in the range of -60 to -30 mV. Thrombin-induced transitions in membrane potential activate the Cav3.1 channel, resulting in a p

Treatment for calcium channel blocker poisoning: a systematic review.

CONTEXT: Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. OBJECTIVE: To evaluate the reported effect … cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected …