British Journal of Pharmacology, Год журнала: 2024, Номер 181(22), С. 4571 - 4592
Опубликована: Авг. 2, 2024
Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but its discontinuation leads to syndrome/catatonia complicated by benzodiazepine-resistance and rhabdomyolysis.
Язык: Английский
British Journal of Pharmacology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 15, 2025
Background and Purpose The antiepileptic drug ethosuximide (ETX) suppresses epileptiform activity in a mouse model of GNB1 syndrome, caused by mutations Gβ 1 protein, likely through the inhibition G‐protein gated K + (GIRK) channels. Here, we investigated mechanism ETX (block) different GIRKs. Experimental Approach We studied GIRK channels expressed Xenopus oocytes with or without their physiological activator, G protein subunit dimer Gβγ. binding site mode action were analysed using molecular dynamic (MD) simulations kinetic modelling, predictions tested mutagenesis functional testing. Key Results show that is subunit‐selective, allosteric blocker potency block increased Gβγ, parallel channel activation. MD locate GIRK2 to region associated phosphatidylinositol‐4,5‐bisphosphate (PIP 2 ) regulation, suggest acts closing helix bundle crossing (HBC) gate altering channel's interaction PIP . apparent affinity highly sensitive changes gating subunits. Conclusion Implications GIRKs allosteric, subunit‐specific, enhanced Gβγ an intricate network interactions within molecule. Our findings pose as potential therapeutic target for potent tool probing gating‐related conformational GIRK.
Язык: Английский
Процитировано
2
British Journal of Pharmacology, Год журнала: 2025, Номер unknown
Опубликована: Фев. 20, 2025
Plasmalemma vesicle-associated protein (PLVAP) regulates transcytosis in vascular endothelial cells. PLVAP expression is increased pathological conditions, such as diabetic retinopathy. P2X7 receptor antagonists have been shown to preserve blood-retinal barrier (BRB) integrity. Here, we tested the hypothesis that tightly linked activity, leading breakdown of BRB an vitro model We integrated network approaches with retinopathy using primary human retinal microvascular cells (HRMECs). Cells were treated a antagonist, JNJ47965567, and several genes predicted belong signalling assessed. Levels localisation PLVAP, VE-cadherin zonula occludens-1 (ZO-1) HRMECs evaluated. In vivo, effects JNJ47965567 on retinas mice High levels glucose HRMECs, which was blocked by JNJ47965567. Furthermore, preserved ZO-1. choroidal vasculature mice, immunostaining increased, compared non-diabetic mice. This increase significantly attenuated treatment CONCLUSIONS AND IMPLICATIONS: study showed important component complex gene regulatory network, including mediating pathophysiology The antagonist good pharmacodynamic profile, suggesting this approach could be value
Язык: Английский
Процитировано
2
British Journal of Pharmacology, Год журнала: 2025, Номер unknown
Опубликована: Фев. 16, 2025
Abstract Background and Purpose Sex‐dependent vascular effects of transient receptor potential (TRP) channels sex dimorphism in migraine are not yet fully characterized. We investigated the differential vasoactive TRP ankyrin 1 (TRPA1), melastatin 3 (TRPM3) vanilloid (TRPV1) channels, their pharmacological mechanism(s), localization expression human isolated blood vessels. Experimental Approach Agonist responses to cinnamaldehyde pregnenolone sulfate (PregS, TRPM3) or capsaicin were analysed using wire myography segments coronary (HCAs) middle meningeal (HMMAs) arteries from men women. The mechanisms involved these antagonists/blockers/inhibitors: HC‐030031 isosakuranetin (TRPM3), capsazepine (TRPV1), olcegepant (calcitonin gene‐related peptide [CGRP] receptor), L‐NAME (nitric oxide synthase [NOS]), indomethacin (cyclooxygenase [COX]), TRAM‐34 + apamin (K channels) MK‐801 ( N ‐methyl‐ d ‐aspartate [NMDA] receptor). Fluorescence microscopy, quantitative polymerase chain reaction (qPCR), western blotting performed investigate location expression, respectively. Key Results In HCAs HMMAs, (i) capsaicin‐induced relaxation remained unchanged after above‐mentioned antagonists/blockers/inhibitors (ii) cinnamaldehyde‐induced was blocked by olcegepant. PregS‐induced maximal significantly enhanced females compared with males inhibited isosakuranetin, L‐NAME. TRPM3 mRNA protein along NMDA levels, higher than males. Conclusion Implications Modulation tone HMMAs activation is sex‐dependent, likely involving receptors. This represents a new therapeutic direction, targeting its related cardiovascular events.
Язык: Английский
Процитировано
1
The Journal of Physiology, Год журнала: 2024, Номер 602(14), С. 3505 - 3518
Опубликована: Май 14, 2024
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Язык: Английский
Процитировано
7
British Journal of Clinical Pharmacology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 15, 2025
Severe valproic acid (VPA) overdose is characterized by coma (sometimes with cerebral oedema), respiratory depression, hypotension and metabolic abnormalities. Traditional management of VPA poisoning has been limited to gastrointestinal decontamination, L-carnitine supplementation and, in severe cases, haemodialysis. Recently, interest developed the use carbapenem antibiotics as an adjunctive therapy patients poisoning. Carbapenems inhibit acylpeptide hydrolase, enzyme responsible for reconstituting from VPA-glucuronide, transiently promote distribution into erythrocytes. In receiving therapeutically, carbapenems lower concentrations abruptly, dramatically, a sustained period. This article discusses possibility exploiting this pharmacokinetic drug-drug interaction or at risk
Язык: Английский
Процитировано
1
CNS Drugs, Год журнала: 2025, Номер unknown
Опубликована: Янв. 24, 2025
Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 play a critical role in modulating susceptibility to seizures, mutations genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation has long been considered an attractive target search for novel antiseizure medications. Ezogabine (retigabine), first Kv7.2/3 activator introduced 2011 treatment focal was withdrawn from market 2017 due declining use after discovery its association with pigmentation changes retina, skin, mucosae. A formulation ezogabine pediatric (XEN496) recently investigated children KCNQ2-related developmental epileptic encephalopathy, but trial terminated prematurely reasons unrelated safety. Among openers clinical development, azetukalner shown dose-dependent efficacy against drug-resistant seizures good tolerability profile no evidence pigmentation-related adverse effects early studies, it is now under investigation phase III trials generalized tonic-clonic major depressive disorder. Another activator, BHV-7000, completed I studies healthy subjects, excellent at plasma drug concentrations exceed median effective preclinical model anticonvulsant activity, data patients are available date. other activators development as potential medications, pynegabine CB-003 have safety pharmacokinetic results not yet reported. Overall, interest targeting indications remains strong. Future breakthroughs area could come exploitation mechanistic differences action activators, molecules combine mechanisms action.
Язык: Английский
Процитировано
1
Molecular Pharmacology, Год журнала: 2025, Номер 107(3), С. 100018 - 100018
Опубликована: Янв. 31, 2025
NS309 (6,7-dichloro-1H-indole-2,3-dione-3-oxime) is widely used as a pharmacological tool to increase the activity of small- and intermediate-conductance calcium-activated potassium channels. assumed function positive allosteric gating modulator. However, its binding site molecular details action remain unknown. Here, we show that has profound effect on calcium-dependent Ca2+-activated K+ channel KCa3.1. In inside-out experiments, 10 μM shifted calcium EC50 from 430 31 nM. whole-cell changing free intracellular 250 nM 3 decreased 74 8.6 We further observed could elicit greater responses than saturating calcium, making it "superagonist." Molecular modeling suggested 2 possible sites for in KCa3.1, which probed by mutagenesis determined interface between S45A segment S4-S5 linker N-lobe channel-associated calmodulin. dynamic simulations revealed pushes several water molecules out pocket, establishes stable contacts with S181 L185 KCa3.1 E54 calmodulin, promotes longer sustained widening inner gate at V282 S6 segment. Polar substitutions hydrophobic-gating residues A279 resulted constitutively open channels not be potentiated NS309, suggesting produces agonistic effects increasing probability SIGNIFICANCE STATEMENT: The publication full-length cryo-electron microscopy structure previously reported was crystallization artifact because this only included C-terminus This study demonstrates true located S4 S5 acts stabilizing force within increases hydrophobic gate.
Язык: Английский
Процитировано
1
British Journal of Pharmacology, Год журнала: 2025, Номер unknown
Опубликована: Фев. 2, 2025
Shear-induced platelet activation and aggregation (SIPA) play crucial roles in arterial thrombosis. Piezo1 is a mechanosensitive calcium channel that promotes hyperactivation under pathological high-shear conditions. This study explores the function of SIPA thrombosis, inhibitory effects mechanisms ginsenoside Rb1 on these processes. Transgenic mice with platelet-specific deficiency (Piezo1ΔPlt) were used to elucidate role A microfluidic system was employed assess aggregation, influx, calpain activity, talin cleavage, integrin αIIbβ3 P-selectin expression shear flow. Cellular thermal shift assay determine binding between Piezo1. Folts-like model evaluate antithrombotic Rb1. platelets reduced induced by high rate 4000 s-1 attenuated thrombosis mouse model. inhibited an IC50 10.8 μM. shear-induced Ca2+-dependent as well thrombus formation Piezo1fl/fl mice. significantly improved stability Treatment Piezo1ΔPlt did not exhibit further Platelet essential for shear. exerted anti-platelet anti-thrombotic at rates via channels, providing potential candidate antiplatelet therapeutic agent.
Язык: Английский
Процитировано
1
British Journal of Pharmacology, Год журнала: 2025, Номер unknown
Опубликована: Фев. 13, 2025
Background and Purpose Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca 2+ influx buffering in early ALS‐affected neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators intracellular , as therapeutic target. Experimental Approach A novel class FKBP12 ligands that show activity cytosolic calcium modulators through stabilizing RyR channel activity, were tested superoxide dismutase 1 (SOD1) G93A mouse model ALS. Different outcomes used to assess efficacy, including electrophysiology, histopathology, neuromuscular function survival. Key Results Among ligands, MP‐010 was chosen for its central nervous system availability favourable vitro pharmaco‐toxicological profile. Chronic administration SOD1 mice produced preservation nerve conduction, 61‐mg·kg −1 dose significantly delaying onset impairment. accompanied improved coordination, increased innervated endplates significant neurones spinal cord treated mice. Notably, extended lifespan an average 10 days compared vehicle. Conclusions Implications particularly MP‐010, exhibit promising neuroprotective effects ALS, highlighting their potential agents. Further investigations into molecular mechanisms clinical translatability these compounds are needed application treatment.
Язык: Английский
Процитировано
1
Pharmacology Research & Perspectives, Год журнала: 2025, Номер 13(2)
Опубликована: Апрель 1, 2025
ABSTRACT β‐adrenergic blockers (β‐blockers) are extensively used to inhibit β‐adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β‐blockers on mouse pancreatic β‐cells. Unexpectedly, high concentrations (100 μM) (propranolol bisoprolol) paradoxically increased levels 5–10 fold, enhanced Ca 2+ influx, stimulated a 2–4 fold increase glucose‐ glimepiride‐induced insulin secretion MIN6‐K8 clonal β‐cells isolated islets. These were observed despite minimal expression β‐adrenoceptors these cells. Mechanistically, led ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering ‐induced release (CICR). CICR then activates transient potential cation channel subfamily M member 5 (TRPM5), resulting influx voltage‐dependent channels. contradict conventional understanding pharmacology β‐blockers, highlighting variability β‐blocker actions depending experimental context.
Язык: Английский
Процитировано
1