The contribution of Na_V1.6 to the efficacy of voltage‐gated sodium channel inhibitors in wild type and Na_V1.6 gain‐of‐function (GOF) mouse seizure control

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(20), P. 3993 - 4011

Published: June 24, 2024

Background and Purpose Inhibitors of voltage‐gated sodium channels (Na V s) are important anti‐epileptic drugs, but the contribution specific channel isoforms is unknown since available inhibitors non‐selective. We aimed to create novel, isoform selective Na v as a means informing development improved antiseizure drugs. Experimental Approach created series compounds with diverse selectivity profiles enabling block 1.6 alone or together 1.2. These novel were evaluated for their ability inhibit electrically evoked seizures in mice heterozygous gain‐of‐function mutation (N1768D/+) Scn8a (encoding 1.6) wild‐type mice. Key Results Pharmacologic inhibition N1768D /+ prevented by 6‐Hz shock. also effective direct current maximal electroshock seizure assay correlated efficacy both models, even without other CNS isoforms. Conclusions Implications Our data suggest driver inhibitor anti‐seizure medicines. Sparing 1.1 inhibitory interneurons did not compromise efficacy. Selective may provide targeted therapies human developmental epileptic encephalopathies treatments idiopathic epilepsies.

Language: Английский

---

Unravelling sources of variability on rocuronium pharmacokinetics: Implications for prolonged recovery in older patients

British Journal of Clinical Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Aims Residual neuromuscular blockade (RNB) commonly occurs when using blockers and increases the risk for pulmonary complications, such as airway obstruction severe hypoxemia, in extubated patients. Rocuronium exhibits a high variability recovery time, contributing to an increased RNB. This study aimed identify characterize sources of rocuronium exposure response via population pharmacokinetic/pharmacodynamic (PK/PD) analysis apply developed PK/PD model investigate clinical implications. Methods A nonlinear mixed‐effect was patients undergoing general anaesthesia, doses 0.3–1.2 mg/kg. Plasma concentrations block (train four ratio) were assessed up 6 h after dosing. The influence age, body mass index, renal function sex on PK PD explored. Simulations performed predict time. Results two‐compartment with linear elimination indirect sigmoid I‐max used describe PD. transfer rate into periphery age. predicted time significantly longer older subjects aged 85 years (median: 2.8 h; interquartile range [IQR]: 2.18–4.0) compared young adults 25 2.5 IQR: 2.0–3.1) following single bolus administrations ≥ 0.7 Conclusions Our findings suggest that take slightly recover than younger due age‐dependent increase tissue uptake. However, priori dose adjustments are not feasible, since age contribution is overshadowed by overall

Language: Английский

---

Carbapenems in the management of valproic acid overdose (MPT‐01166‐24 R1)

British Journal of Clinical Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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

Language: Английский

---

Ethosuximide: Subunit‐ and Gβγ‐dependent blocker and reporter of allosteric changes in GIRK channels

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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.

Language: Английский

---

Actions of dexmedetomidine in regulating NLRP3 in postoperative cognitive dysfunction in aged mice via the autophagy–lysosome pathway

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Autophagy-lysosomal pathway dysfunction leads to postoperative cognitive (POCD). Dexmedetomidine (Dex) improves POCD, and we probed the effects of Dex on autophagy-lysosomal in a POCD model. A mouse model was established intraperitoneally injected with Dex. Cognitive function evaluated by Morris water maze/open field test/novel object recognition assay. Levels neurotransmitters/inflammatory cytokines hippocampus, NLRP3/ASC/Cleaved Caspase-1 proteins were determined ELISA/Western blot. NLRP3 inflammasome-mediated microglial activation/astrocyte A1 differentiation hippocampal CA1 region assessed immunofluorescence BV-2 cells treated lipopolysaccharide (LPS) and/or inflammasome activator Nigericin, transfected si-TFEB for co-culture primary reactive astrocytes (RAs) verify vitro. alleviated mice repressed activation astrocyte differentiation. partially reversed protective effect condition. In vitro experiments verified inhibitory properties induces TFEB nuclear translocation, autophagy lysosomal biogenesis. By activating autophagy-lysosome pathway, regulated activation, inhibited vivo. regulates promoting translocation inhibits differentiation, thereby alleviating POCD.

Language: Английский

---

Toll‐like receptor 4 deficiency ameliorates experimental ileitis and enteric neuropathy: Involvement of nitrergic and 5‐hydroxytryptaminergic neurotransmission

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Background and Purpose Inflammatory bowel disease (IBD) patients display genetic polymorphisms in toll‐like receptor 4 (TLR4) genes, contributing to dysregulate enteric nervous system (ENS) circuits with increased levels of 5‐HT alteration the neuroimmune crosstalk. In this study, we investigated impact TLR4 signalling on mouse ENS dysfunction caused by dextran sulphate sodium (DSS)‐induced ileitis. Experimental Approach Male C57BL/6J (wild‐type [WT]) −/− mice (10 ± 2 weeks old) received 2% DSS drinking water for 5 days then were switched 3‐day regular water. Histological analysis proinflammatory cytokine mRNA assessed ileal samples. Gut motility was evaluated changes transit a fluorescent‐labelled marker isometric neuromuscular responses full‐thickness segments non‐receptor‐mediated stimuli. Alterations architecture confocal immunohistochemistry longitudinal muscle–myenteric plexus whole‐mount preparations. Key Results WT mice, treatment delayed gastrointestinal transit, myenteric neurodegeneration, reactive gliosis release cytokines. Enhanced cholinergic tachykinergic excitatory tone, inducible nitric oxide synthase (iNOS)‐mediated relaxation, 2A 3 receptor‐mediated observed during ileitis mice. deficiency reversed most functional morphological abnormalities. Conclusion Implications Our results demonstrate that activity influences severity ileitis, neuroglial plasticity, gut motility, nitrergic 5‐HTergic neurotransmissions. The interaction between our study appears be potential pharmacological target treat implicated IBD onset/progression.

Language: Английский

---

NS309 Functions as a Superagonist for the Calcium-Activated Potassium Channel KCa3.1

Molecular Pharmacology, Journal Year: 2025, Volume and Issue: 107(3), P. 100018 - 100018

Published: Jan. 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.

Language: Английский

---

Involvement of Piezo 1 in inhibition of shear‐induced platelet activation and arterial thrombosis by ginsenoside Rb1

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

---

Involvement of the somatosensory‐autonomic reflex and muscarinic receptors in exacerbation of allergic pulmonary inflammation by electroacupuncture

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 9, 2025

Background and Purpose Emerging evidence suggests that electroacupuncture (EA) could cause autonomic reflexes to modulate visceral functions. However, the efficacy underlying mechanisms for somatic stimulation on allergic pulmonary inflammation (API) remain elusive. Experimental Approach Mice were administered intranasal Papain induce API. Distinct current (0,0.1, 0.2 0.5 mA) of EA at back BL13, hindlimb ST36 forelimb LU5 acupoint then carried out. The control group underwent same procedure but without stimulation. Changes in API was assessed using immunohistochemistry, flow cytometry haematoxylin eosin (H&E) staining. Pharmacological approaches used investigate effects Key Results region not limb regions, a intensity‐dependent manner, exacerbated API, primarily causing decrease survival rate intensified lung, including infiltration lung type 2 innate lymphoid cells eosinophils, pathology scores. Blocking local thoracic sensory nerves with lidocaine or lung‐innervated hexamethonium eliminates EA‐produced detrimental effects. Chemical sympathectomy 6‐OHDA further enhanced scores, inhibiting activity muscarinic receptors sufficient prevent exacerbation induced by EA. Conclusion Implications Our findings suggest BL13 induces somatic‐autonomic reflex involving receptors, thereby exacerbating selective intensity‐dependency activation body regions driving pathways help optimise parameters, enhancing both safety modulating

Language: Английский

---

Chemosensory signalling in human sperm is controlled by Ca²⁺ influx via CatSper and Ca²⁺ clearance via plasma membrane Ca²⁺ ATPases

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Loss of function the sperm-specific Ca2+ channel CatSper is a common channelopathy that causes male infertility. controls intracellular concentration and, thereby, motility human sperm. Activation by oviductal ligands evokes transient increase, which entails changes in flagellar beat are required for fertilisation. The CatSper-mediated influx has been studied extensively, whereas mechanisms underlying clearance and recovery from have remained ill-defined. We examined how pharmacological suppression export cytosol into extracellular space or uptake stores affects resting signals sperm healthy volunteers infertile men lacking functional channels, using kinetic Ca2+- pH-fluorometry as well patch-clamp recordings. show entering via predominantly, if not exclusively, exported plasma membrane ATPases (PMCAs). Na+/Ca2+ exchange mitochondria play no only negligible role signalling controlled interplay PMCAs, is, balance between

Language: Английский

---