Blockade of P2X7 receptors preserves blood retinal barrier integrity by modulating the plasmalemma vesicle‐associated protein: Implications for diabetic retinopathy

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

Published: Feb. 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

Language: Английский

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Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1^G93A amyotrophic lateral sclerosis (ALS) mice

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

Published: Feb. 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.

Language: Английский

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Sex differences in the vasoactive effect of transient receptor potential channels: TRPM3 as a new therapeutic target for (neuro)vascular disorders

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

Published: Feb. 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.

Language: Английский

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Role of Na_V1.7 in postganglionic sympathetic nerve function in human and guinea‐pig arteries

The Journal of Physiology, Journal Year: 2024, Volume and Issue: 602(14), P. 3505 - 3518

Published: May 14, 2024

Na

Language: Английский

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Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(15), P. 2413 - 2428

Published: May 21, 2024

Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI foetuses remain unknown. Thus the effect maternally administered on foetal genetic structural development was investigated.

Language: Английский

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Advancing the field of viroporins—Structure, function and pharmacology: IUPHAR Review 39

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(22), P. 4450 - 4490

Published: Sept. 3, 2024

Viroporins possess important potential as antiviral targets due to their critical roles during virus life cycles, spanning from entry egress. Although the amantadine M2 viroporin of influenza A virus, successful progression other inhibitors into clinical use remains challenging. These challenges relate in varying proportions a lack reliable full‐length 3D‐structures, difficulties functionally characterising individual viroporins, and absence verifiable direct binding between inhibitor viroporin. This review offers perspectives help overcome these challenges. We provide comprehensive overview family, including structural functional features, highlighting moldability energy landscapes actions. To advance field, we suggest list best practices aspire towards unambiguous identification characterisation, along with considerations pitfalls. Finally, present current future scenarios of, prospects for, targeting drugs.

Language: Английский

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Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(13), P. 2070 - 2084

Published: March 25, 2024

Background and Purpose Kratom is a preparation from Mitragyna speciosa , which used as natural drug for many purposes around the world. However, an overdose of may cause addiction‐like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid mitragynine, showing opioid‐like properties. Experimental Approach Here, we analysed neuropharmacological effects mitragynine compared with morphine rats searched pharmacological treatment option that reverse occurring deficits usually aggravate withdrawal. Key Results We found 14‐day (1–10 mg·kg −1 ·day ) caused dose‐dependent behavioural signs resembling those (5 10 also induced passive avoidance task. Mitragynine not only reduced hippocampal field excitatory postsynaptic potential (fEPSP) amplitudes basal synaptic transmission long‐term potentiation (LTP) but epigenetic markers, such histone H3K9 H4K12 expression. At same time, it up‐regulates HDAC2 Targeting adaptations HDAC inhibitor, SAHA reversed on dysregulation, input/output curves, paired‐pulse facilitation, LTP attenuated deficit. amplified Conclusion Implications The data this work show changes expression downstream plasticity explain morphine, behaviours impairments. Thus, provide new approach Kratom/mitragynine addiction.

Language: Английский

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Topical application of a P2X2/P2X3 purine receptor inhibitor suppresses the bitter taste of medicines and other taste qualities

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(17), P. 3282 - 3299

Published: May 14, 2024

Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need develop bitter blockers suppress the of vital medications. Bitter mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets TAS2Rs, targeting specific receptors may only for certain, but not all, bitter-tasting compounds. Alternative strategies are needed identify universal that will improve acceptance every medication. Taste cells mouth transmit signals afferent gustatory nerve fibres through release ATP, which activates nerve-expressed purine P2X2/P2X3. We hypothesized blocking transmission with P2X2/P2X3 inhibitors (e.g. 5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine [AF-353]) would reduce all and

Language: Английский

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Schwann cell TRPA1 elicits reserpine‐induced fibromyalgia pain in mice

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(18), P. 3445 - 3461

Published: May 21, 2024

Background and Purpose Fibromyalgia is a complex clinical disorder with an unknown aetiology, characterized by generalized pain co‐morbid symptoms such as anxiety depression. An imbalance of oxidants antioxidants proposed to play pivotal role in the pathogenesis fibromyalgia symptoms. However, precise mechanisms which oxidative stress contributes fibromyalgia‐induced remain unclear. The transient receptor potential ankyrin 1 (TRPA1) channel, known both sensor sensor, has been implicated various painful conditions. Experimental Approach feed‐forward mechanism that implicates reactive oxygen species (ROS) driven TRPA1 was investigated reserpine‐induced model C57BL/6J mice employing pharmacological interventions genetic approaches. Key Results Reserpine‐treated developed pain‐like behaviours (mechanical/cold hypersensitivity) early anxiety‐depressive‐like disorders, accompanied increased levels markers sciatic nerve tissues. These effects were not observed upon blockade or global deletion channel macrophage depletion. Furthermore, we demonstrated selective silencing Schwann cells reduced neuroinflammation (NADPH oxidase 1‐dependent ROS generation increase nerve) attenuated fibromyalgia‐like behaviours. Conclusion Implications Activated expressing promote intracellular pathway culminating release recruitment macrophages mouse nerve. cellular molecular events sustain mechanical cold hypersensitivity reserpine‐evoked model. Targeting channels on could offer novel therapeutic approach for managing fibromyalgia‐related

Language: Английский

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The mitochondrial calcium uniporter inhibitor Ru265 increases neuronal excitability and reduces neurotransmission via off‐target effects

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(18), P. 3503 - 3526

Published: May 23, 2024

Abstract Background and Purpose Excitotoxicity due to mitochondrial calcium (Ca 2+ ) overloading can trigger neuronal cell death in a variety of pathologies. Inhibiting the uniporter (MCU) has been proposed as therapeutic avenue prevent overloading. Ru265 (ClRu(NH 3 4 (μ‐N)Ru(NH Cl]Cl is cell‐permeable inhibitor with nanomolar affinity. reduces sensorimotor deficits models ischemic stroke. However, use limited by induction seizure‐like behaviours. Experimental Approach We examined effect on synaptic function acute brain slices hippocampal neuron cultures derived from mice, control where MCU expression was genetically abrogated. Key Results decreased evoked responses calyx terminals induced spontaneous action potential firing both terminal postsynaptic principal cell. Recordings presynaptic Ca currents suggested that blocks P/Q type channel, confirmed inhibition cells exogenously expressing channel. Measurements K + further revealed blocked KCNQ current, leading increased membrane excitability, underlying spiking. imaging neurons showed synchronized, high‐amplitude events, recapitulating activity seen vivo . Importantly, ablation did not suppress Ru265‐induced increases seizures. Conclusions Implications Our findings provide mechanistic explanation for pro‐convulsant effects suggest counter screening assays based measurement channel identify safe inhibitors.

Language: Английский

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