N-type calcium channels antagonists

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (20): 7482-7492. DOI: 10.26355/eurrev_202210_30018-PMID: 36314318, published online on October 28, 2022. After publication, the authors applied some corrections to the text: - The section "Clinical Oharmacology of Lercanidipine" has been corrected into "Clinical Pharmacology of Lercanidipine" - The Legend of Figure 2 has been corrected as follows: Ca T-type channels vs. Ca L-type channels selectivity ratio. LAC, lacidipine, AML, amlodipine; MIB, mibefradil; LER, lercanidipine; *p<0...

The possible role of voltage-sensitive calcium channels (VSCC) activation in the glufosinate ammonium (GLA)-induced dopamine release was investigated using selective VSCC blockers and the dopamine levels were measured by HPLC from samples obtained by in vivo cerebral microdialysis. While pretreatment with 10μM flunarizine (T-type VSCC antagonist) or nicardipine (L-type VSCC antagonist) had no statistically significant effect on dopamine release induced by 10mM GLA, pretreatment with 100μM of both antagonists, or 20 μM ω-conotoxin MVIIC (non-selective P/Q-type VSCC antagonist) significantly decreased the GLA-induced dopamine release over 72...

Depression is a severe mental health problem that affects people regardless of social status or education, is associated with changes in mood and behavior, and can result in a suicide attempt. Therapy of depressive disorders is based mainly on drugs discovered in the 1960s and early 1970s. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are frontline pharmacological strategies for the medical treatment of depression. In addition, approved by FDA in 2019, esketamine [as nasal spray; N-methyl-D-aspartate (NMDA) receptors antagonist with additional effects on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, L-type voltage-dependent calcium channel (L-VDCC), opioid receptors, and monoaminergic receptors] is an essential compound in suicide and drug-resistant depression...

The analgesic α -conotoxins Vc1.1, RgIA, and PeIA attenuate nociceptive transmission via activation of G protein-coupled GABAB receptors (GABAB Rs) to modulate N-type calcium channels in primary afferent neurons and recombinantly coexpressed human GABAB R and Cav2.2 channels in human embryonic kidney 293T cells. Here, we investigate the effects of analgesic α -conotoxins following the mutation of amino acid residues in the Venus flytrap (VFT) domains of the GABAB R subunits predicted through computational peptide docking and molecular dynamics simulations...

Calcium is one of the most vital intracellular secondary messengers that tightly regulates a variety of cell physiology processes, especially in the brain. Using a fluorescent Ca2+ -sensitive Oregon Green probe, we revealed three different amplitude distributions of spontaneous Ca2+ events (SCEs) in neurons between 15-26 days in vitro (DIV) culture maturation. We detected a series of amplitude events: micro amplitude SCE (microSCE) 25% increase from the baseline, intermediate amplitude SCE (interSCE) as 25-75%, and macro amplitude SCE (macroSCE) - over 75%...

Hypertension predisposes patients to a cluster of deadly cardiovascular and metabolic diseases involving inflammation, dyslipidemia, and fluid imbalance. Current medications fail to normalize blood pressure in 25% of hypertensive patients; therefore, we considered the possibility that the lymphatic circulation provides a new therapeutic target to alleviate hypertension and its associated co-morbidities. The intrinsic driving force for the propulsion of lymph fluid is the robust, spontaneous rhythmic contractions of lymphatic muscle cells (LMCs) that facilitate the lymph flow which helps maintain fluid balance and the transport of lipids and immune cells...

Ligands of the Gi protein-coupled adenosine A3 receptor (A3 R) are receiving increasing interest as attractive therapeutic tools for the treatment of a number of pathological conditions of the central and peripheral nervous systems (CNS and PNS, respectively). Their safe pharmacological profiles emerging from clinical trials on different pathologies (e.g., rheumatoid arthritis, psoriasis and fatty liver diseases) confer a realistic translational potential to these compounds, thus encouraging the investigation of highly selective agonists and antagonists of A3 R...

We systematically reviewed randomized controlled trials (RCTs) that consider the effect of initial dual antihypertensive combination treatment on blood pressure (BP), morbidity, or mortality in hypertensive African ancestry adults, using the methodology of the Cochrane Collaboration. Main outcomes were difference in means (continuous data) and risk ratio (dichotomous data).We retrieved 1728 reports yielding 13 RCTs of 4 weeks to 3 years duration (median 8 weeks) in 3843 patients. Systolic BP was significantly higher on β-adrenergic blocker vs...

Both inhibitory and excitatory GABA transmission exist in the mature suprachiasmatic nucleus (SCN), the master pacemaker of circadian physiology. Whether GABA is inhibitory or excitatory depends on the intracellular chloride concentration ([Cl- ]i ). Here, using the genetically encoded ratiometric probe Cl-Sensor, we investigated [Cl- ]i in AVP and VIP-expressing SCN neurons for several days in culture. The chloride ratio (RCl ) demonstrated circadian rhythmicity in AVP + neurons and VIP + neurons, but was not detected in GFAP + astrocytes...

There are reports regarding the effects of intracellular Ca2+ and synthesis and release of endocannabinoids. The secretion of endocannabinoids depends on the L-type calcium channel. The present study evaluated the involvement of the cannabinoid CB1 receptors in the effect of L-type calcium channel blocker verapamil on passive avoidance learning (PAL) in adult male rats. In this study, we examined the effects of an acute administration of the cannabinoid CB1 receptors antagonist/inverse agonist AM251 following a chronic administration of the Ca2+ channel blocker verapamil on PAL...

BACKGROUND: Cannabinoid type-1 receptors (CB1 Rs) are expressed in primary sensory neurones, but their role in pain modulation remains unclear. METHODS: We produced Pirt-CB1 R conditional knockout (cKO) mice to delete CB1 Rs in primary sensory neurones selectively, and used behavioural, pharmacological, and electrophysiological approaches to examine the influence of peripheral CB1 R signalling on nociceptive and inflammatory pain. RESULTS: Conditional knockout of Pirt-CB1 R did not alter mechanical or heat nociceptive thresholds, complete Freund adjuvant-induced inflammation, or heat hyperalgesia in vivo...

αO-Conotoxin GeXIVA is a 28 amino acid peptide derived from the venom of the marine snail Conus generalis. The presence of four cysteine residues in the structure of GeXIVA allows it to have three different disulfide isomers, that is, the globular, ribbon or bead isomer. All three isomers are active at α9α10 nicotinic acetylcholine receptors, with the bead isomer, GeXIVA[1,2], being the most potent and exhibiting analgesic activity in animal models of neuropathic pain. The original report of GeXIVA activity failed to observe any effect of the isomers on high voltage-activated (HVA) calcium channel currents in rat dorsal root ganglion (DRG) neurons...

L-type Ca2+ channels (LTCCs) are key elements in electromechanical coupling in striated muscles and formation of neuromuscular junctions (NMJs). However, the significance of LTCCs in regulation of neurotransmitter release is still far from understanding. Here, we found that LTCCs can increase evoked neurotransmitter release (especially asynchronous component) and spontaneous exocytosis in two functionally different compartment of the frog NMJ, namely distal and proximal parts. The effects of LTCC blockage on evoked and spontaneous release as well as timing of exocytotic events were prevented by inhibition of either protein kinase C (PKC) or P2Y receptors (P2Y-Rs)...

ω -Conotoxins inhibit N-type voltage-gated calcium (CaV 2.2) channels and exhibit efficacy in attenuating neuropathic pain but have a low therapeutic index. Here, we synthesized and characterized a novel ω -conotoxin, Bu8 from Conus bullatus , which consists of 25 amino acid residues and three disulfide bridges. Bu8 selectively and potently inhibits depolarization-activated Ba2+ currents mediated by rat CaV 2.2 expressed in HEK293T cells (IC50  = 89 nmol/L). Bu8 is two-fold more potent than ω -conotoxin MVIIA, a ω -conotoxin currently used for the treatment of severe chronic pain...

The mitochondrial inhibitor 3-nitropropionic acid (3-NP) induces excitotoxicity. The authors hypothesized that CTK 01512-2, a recombinant peptide calcium channel N-type blocker, and the TRPA1 antagonist, could show neuroprotective effects. The male Wistar rats received 3-NP [25 mg/kg (i.p.) for 7 days], and a treatment of CTK 01512-2 was delivered intrathecally (i.t.), thrice a week. The neuroprotective effects were evaluated by [18 F]FDG MicroPET analysis. The CTK 01512-2 toxin was able to reestablish similar glucose uptakes on the control animals...

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV 2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood...

Rosmarinic acid, a major component of rosemary, is a polyphenolic compound with potential neuroprotective effects. Asreducing the synaptic release of glutamate is crucial to achieving neuroprotectant's pharmacotherapeutic effects, the effect of rosmarinic acid on glutamate release was investigated in rat cerebrocortical nerve terminals (synaptosomes). Rosmarinic acid depressed the 4-aminopyridine (4-AP)-induced glutamate release in a concentration-dependent manner. The removal of extracellular calcium and the blockade of vesicular transporters prevented the inhibition of glutamate release by rosmarinic acid...

Histamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H2 -histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H2 -histamine receptors in a cardiac-specific way (H2 -TG) in comparison with their wild-type (WT) littermate controls...

Subtypes (1-4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects. Currently, in the least shew model of emesis we find that ZD7288 induces vomiting in a dose-dependent manner, with maximal efficacies of 100% at 1 mg/kg (i...

The suitability of a newly developed cell-based functional assay was tested for the detection of the activity of a range of neurotoxins and neuroactive pharmaceuticals which act by stimulation or inhibition of calcium-dependent neurotransmitter release. In this functional assay, a reporter enzyme is released concomitantly with the neurotransmitter from neurosecretory vesicles. The current study showed that the release of a luciferase from a differentiated human neuroblastoma-based reporter cell line (SIMA-hPOMC1-26-GLuc cells) can be stimulated by a carbachol-mediated activation of the Gq-coupled muscarinic-acetylcholine receptor and by the Ca2+ -channel forming spider toxin α-latrotoxin...