bioRxiv - Pharmacology and Toxicology最新文献

{"title":"Quinoline synergy and reduced use: a study of pharmacodynamic interactions","authors":"Zahra Sadouki, Emmanuel Q Wey, Timothy D McHugh, Frank Kloprogge","doi":"10.1101/2024.09.13.612836","DOIUrl":"https://doi.org/10.1101/2024.09.13.612836","url":null,"abstract":"Background: Meropenem, gentamicin and ciprofloxacin have been used as empiric broad-spectrum combination therapy in different combinations. Recent restrictions on the use of quinolones jeopardises the rational of administering this combination to increase the spectrum of coverage for this particular case. A mechanistic understanding of pharmacodynamic interaction for these combinations is lacking but can provide insight in the necessity of using the different moieties. Objectives: To study pharmacodynamic drug-drug interaction between meropenem, gentamicin and ciprofloxacin against Escherichia coli.\u0000Methods: Static time kill curve experiments were conducted with Escherichia coli (NCTC 12241) at 0.25 - 16 x MIC for a duration of 24 hours with samples being collected at 0, 2, 4, 6, 8, and 24 hour. Meropenem, gentamicin and ciprofloxacin were tested alone, in two- and three-way combinations. Bacterial load time series data were enumerated on Meuller Hinton plates and Colony Forming Unit data was modelled using nonlinear mixed-effects models in nlmixr.\u0000Results: Meropenem, gentamicin and ciprofloxacin two- and three-way combinations prevented regrowth, but did not when these moieties were studied alone. Gentamicin and meropenem were synergistic by decreasing ciprofloxacin IC50 and the combination effects of meropenem and gentamicin and the addition of meropenem on top of a gentamicin and ciprofloxacin combination were indifferent. Conclusions: Our findings emphasize the added value of a quinolone in the drug combination. In light of the recent move towards reduced use of quinolones, a quinolone free combination still prevented regrowth, it just did not display further synergy on IC50 and was indifferent in initial killing.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in vivo evaluation of Ulva lactuca for wound healing","authors":"Chien-Hsing Wang, Zih-Ting Huang, Kuo-Feng Tai","doi":"10.1101/2024.09.13.612816","DOIUrl":"https://doi.org/10.1101/2024.09.13.612816","url":null,"abstract":"Ulva lactuca (U. lactuca) is an important seaweed species. Some ingredients in these seaweeds are thought to accelerate wound healing. However, limited data on the use of seaweed for wound healing exists. This study examined whether ethanol or aqueous extracts of U. lactuca promote antioxidant and anti-inflammatory properties in vitro and wound healing in vitro and in vivo. Cell proliferation, antioxidation, and migration were observed in NIH3T3 cells treated with U. lactuca extract in vitro. Both U. lactuca extracts were examined for their ability to inhibit inflammatory cytokine synthesis in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In vivo experiments involved four groups of albino mice (BALB/c; 10 mice per group). One 1.0 cm2 wound was created via excision of full-thickness skin on the back of all mice. Mice in Group I mice were treated topically with the ethanol extract of U. lactuca (25 mg/mL) for 10 d. group II mice were treated topically with an aqueous extract of U. lactuca (12.5 mg/mL) for 10 d. Group III received topical application of phosphate-buffered saline solution. Group IV wounds were maintained without treatment. Both extracts significantly increased fibroblast proliferation. The antioxidant activity of the U. lactuca extract was determined using a total antioxidant capacity assay. Both extracts inhibited the release of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-?? from LPS-mediated inflammation in RAW 264.7 cells. These extracts also upregulated the expression of Th2 cytokines such as transforming growth factor beta 1 (TGF-β1) and interleukin 10 (IL-10) in RAW 264.7 cells under pro-inflammatory conditions. Both extracts enhanced the migratory ability of NIH3T3 cells. U. lactuca ethanol extract enhances wound healing properties in vivo. These results suggest that bioactive compounds derived from U. lactuca extract are beneficial for wound healing and anti-inflammatory therapies.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"214 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Evaluation of Anti-Inflammatory, Anti-Plaque Efficacy, and Biocompatibility of Norway Spruce (Picea abies) Resin Extract for Oral Care Applications","authors":"Kamilla Yamileva, Simone Parrotta, Evgen Multia","doi":"10.1101/2024.09.17.613464","DOIUrl":"https://doi.org/10.1101/2024.09.17.613464","url":null,"abstract":"The periodontal disease is globally highly prevalent, and calls for novel, effective, and preferably bio-based raw materials. Accumulation of dental plaque causes gingivitis, which is reversible by treatments that control the bacterial biofilm. If left untreated, the gingivitis can lead to gingival inflammation and potentially progress to periodontitis. In this study, a natural antimicrobial and anti-inflammatory Norway spruce (Picea abies) resin extract was evaluated as a potential option in supportive periodontal care. Lipopolysaccharide-induced macrophage-like cells were used to study the anti-inflammatory properties in vitro. The spruce resin extract at 20% concentration had the highest anti-inflammatory effect, comparable to a corticosteroid's effect on pro-inflammatory cytokines interleukin-1 beta (IL-beta), tumor necrosis factor-alpha (TNF-alpha), and matrix metalloproteinase-3 (MMP-3). Consequently, the 20% spruce resin extract was selected for toothpaste formulation. Its anti-plaque efficacy was evaluated by total aerobic colony counts and the proportions of streptococci grown on the surfaces of the treated glass rods using pooled human saliva. It was found that the toothpaste effectively reduced dental plaque biofilm, matching the anti-plaque efficacy of Corsodyl mouthwash, containing chlorhexidine digluconate. The toothpaste was also found to be non-corrosive in biocompatibility studies on three-dimensional (3D) models of human oral and gingival epithelium. These findings provide scientific validation of spruce resin's effectiveness in oral care, elucidating probable reasons why people have historically chewed resins for oral care purposes.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daphnids Can Safeguard the Use of Alternative Bioassays to the Acute Fish Toxicity Test: A Focus on Neurotoxicity","authors":"Christoph Schuer, Martin Paparella, Christopher Fassbender, Gilly Stoddart, Marco Baity-Jesi, Kristin Schirmer","doi":"10.1101/2024.09.12.612652","DOIUrl":"https://doi.org/10.1101/2024.09.12.612652","url":null,"abstract":"Assessment of potential impacts of chemicals on the environment traditionally involves regulatory standard data requirements for acute aquatic toxicity testing using algae, daphnids and fish (e.g., OECD test guidelines (TG) 201, 202, and 203, respectively), representing different trophic levels. In line with the societal goal to replace or reduce vertebrate animal testing, alternative bioassays were developed to replace testing with fish: the fish cell line RTgill-W1 acute toxicity assay (OECD TG249) and the zebrafish embryo acute toxicity test (zFET, OECD TG236). However, previous studies revealed the lower sensitivity of the RTgill-W1 cell line assay and zFET for some neurotoxic chemicals and allyl alcohol, which is presumably biotransformed in fish to the more toxic acrolein (which is predicted well through the cell line assay). To provide an additional alternative to acute fish toxicity, in this study, we analyzed historic ecotoxicity data for fish and daphnids from the EnviroTox Database. We found a considerable variability in acute fish LC50 and acute daphnids EC50 values, particularly for neurotoxic chemicals. Comparing sensitivity of these taxonomic groups according to different neurotoxicity classification schemes indicates that fish rarely represent the most sensitive trophic level of the two. Exceptions here most prominently include a few cyclodiene compounds, which are no longer marketed, and a chemical group that could be identified through structural alerts. Moreover, daphnids are more sensitive than fish to acrolein. This analysis highlights the potential of the Daphnia acute toxicity test, which is usually a standard regulatory data requirement, in safeguarding the environmental protection level provided by the RTgill-W1 cell line assay and the zFET. This research, rooted in decades of efforts to replace the fish acute toxicity test, shifts the focus from predicting fish toxicity 1-to-1 to emphasizing the protectiveness of alternative methods, paving the way for further eliminating vertebrate tests in environmental toxicology.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Qing-Luo-Yin-induced SIRT1 inhibition contributes to the immune improvement of adjuvant-induced arthritis rats","authors":"Jian Zuo, Zhe Yang","doi":"10.1101/2024.09.13.608378","DOIUrl":"https://doi.org/10.1101/2024.09.13.608378","url":null,"abstract":"The herbal formula Qing-Luo-Yin (QLY) was proved containing SIRT1 inhibitors. Whether they contribute to the anti-rheumatic effects is to be confirmed. Adjuvant-induced arthritis (AIA) rats were treated by QLY or/and nicotinamide mononucleotide (NMN) for 38 days. After sacrifice, main tissues were collected for histological and western-blot experiments. Levels of rheumatoid arthritis (RA)-related indictors in blood or tissue homogenates were detected by commercial kits. Normal pre-adipocytes were cultured by the relevant rat serums, and the medium was collected for monocytes culture. In replicate experiments, some pre-adipocytes received additional compounds or SIRT1 silencing/overexpression treatments. Due to spontaneous remission of inflammation, QLY did not further improve immune milieu in AIA rats, but greatly eased paw edema and joint injuries. Besides, it reversed triglyceride/glucose depletion in liver and adipose tissues, and inhibited the expression and function of SIRT1, causing concomitant changes of related signals and adipkines production. All the effects were weakened by NMN, which activated SIRT1 by increasing NAD production. in the monocytes cultured with the corresponding medium. A mixture of matrine, sinomenine, sophocarpine, dioscin, berberine showed the similar effects on pre-adipocytes to QLY-containing serum. eNAMPT decrease was especially notable, which was obviously weakened by SIRT1 overexpression but overshadowed SIRT1-silencing. SIRT1 inhibitors in QLY reshaped metabolism and secretion profiles of adipose tissues. It consequently mitigated eNAMPT-mediated inflammation and eased AIA in rats.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Topical Ophthalmic Administration of VIAN-c4551 Antiangiogenic Peptide for Diabetic Macular Edema: Preclinical Efficacy and Ocular Pharmacokinetics","authors":"Elva Adán-Castro, Magdalena Zamora, Daniela Granados-Carrasco, Lourdes Siqueiros-Márquez, Jose F. García-Rodrigo, Thomas Bertsch, Jakob Triebel, Gonzalo Martínez de la Escalera, Juan Pablo Robles, Carmen Clapp","doi":"10.1101/2024.09.11.612517","DOIUrl":"https://doi.org/10.1101/2024.09.11.612517","url":null,"abstract":"VIAN-c4551 is a cyclic antiangiogenic peptide that stands as a potent and stable inhibitor of vascular endothelial cell growth factor (VEGF), the major vasopermeability and angiogenic factor in diabetic macular edema and diabetic retinopathy. Intravitreal injections of inhibitors of VEGF are a first-line therapy, but the invasiveness, risk, and low adherence of frequent intravitreal injections interfere with the needed long-term treatments and successful outcomes. Eye drops are non-invasive and favor compliance. Here, we evaluated the preclinical efficacy, permeability, and ocular pharmacokinetics of VIAN-c4551 delivered in eye drops. VIAN-c4551 demonstrated high potency (IC₅₀ = 137 pM) to inhibit the permeability of human umbilical vein endothelial cell monolayers induced by VEGF. VIAN-c4551 eye drops potently (0.005% minimum effective dose) prevented the retinal vascular leakage induced by VEGF injected intravitreally for up to 24 hours and reversed the increase in retinal vascular permeability due to streptozotocin-induced diabetes in rats and mice. VIAN-c4551 exhibited high permeability across MDCK epithelium and, after a single topical ocular instillation in rabbits, reached the retina-choroid in micromolar concentrations several orders of magnitude above its IC₅₀ (C_max= 51 μM at 6 hours) that lasted at least 24 hours. In conclusion, VIAN-c4551 eye drops reach the back of the eye at therapeutic concentrations, providing a potential, once-a-day, non-invasive intervention for preventing and reversing retinal vascular leakage in diabetic macular edema, diabetic retinopathy, and other vascular retinopathies and preserving sight.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conditional Localization Pharmacology Manipulates the Cell Cycle with Spatiotemporal Precision","authors":"Changfeng Deng, Yung-Chi Lan, Geng-Yuan Chen, Chigozie S Ekeabu, Megan Chung, Michael Lampson, David M. Chenoweth","doi":"10.1101/2024.09.12.612697","DOIUrl":"https://doi.org/10.1101/2024.09.12.612697","url":null,"abstract":"Traditional pharmacology has limited control of drug activity and localization in space and time. Herein, we described an approach for kinase regulation using conditional localization pharmacology (CLP), where an inactive caged inhibitor is localized to a site of interest in a dormant state using intracellular protein tethering. The activity of the inhibitor can be regulated with spatial and temporal precision in a live cellular environment using light. As a proof of concept, a photocaged MPS1 kinase inhibitor (reversine) bearing a Halo-tag ligand tether was designed to manipulate the cell cycle. We demonstrate that this new caged reversine halo probe (CRH) strategy is capable of efficient localization and exceptional spatiotemporal control over spindle assembly checkpoint (SAC) silencing and mitotic exit.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing The Fabrication Of Shape-Defined Microparticles For Sustained Drug Delivery: The 'Less Is More' Paradigm","authors":"Denise Murgia, Bianca Martins Estevao, Corinne Portioli, Roberto Palomba, Paolo Decuzzi","doi":"10.1101/2024.09.10.612107","DOIUrl":"https://doi.org/10.1101/2024.09.10.612107","url":null,"abstract":"Polymeric microparticles find extensive use in several pharmaceutical applications. Our group has developed poly(lactic-co-glycolic acid) (PLGA) microPLates (μPL) featuring a square base of 20 × 20 μm and a height of 10 μm for the controlled and sustained delivery of a range of therapeutic payloads, including anti-inflammatory and anti-cancer drugs, small molecules for neurodevelopmental disorders, and siRNA for osteoarthritis. In this study, the morphological and pharmacological properties of PLGA-μPL were optimized by introducing new steps in the original fabrication protocol and systematically varying the polymer content. Vacuum suction was used to control solvent removal, and two different \"cleaning\" steps were tested, resulting in six different μPL configurations with a PLGA content ranging from 2 to 10 mg. Electron and optical microscopy analyses confirmed the well-defined square shape of μPL, with a central concavity depending on the PLGA content. Fabrication yielding ranged between 10% and 70%, while encapsulation efficiencies reached approximately 15% using curcumin (CURC) as a model drug. The kinetics of CURC release was analyzed using the semi-empirical model of Korsmeyer-Peppas, suggesting either a Fickian diffusion or anomalous transport mechanisms based on the PLGA amounts. Complementary techniques were used to assess morphological alterations and mass loss, evaluating the degradation μPL over time in water and physiological solutions. Unexpectedly, μPL configurations with lower PLGA contents exhibited higher fabrication yielding, drug encapsulation, and slower drug release. The optimized fabrication approach offers greater flexibility to tailor the degradation and pharmacological properties of μPL for various therapeutic applications.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing NADPH to Restore Redox Homeostasis and Lysosomal Function in G6PD-Deficient Microglia","authors":"Abir Mondal, Soumyadeep Mukherjee, Prince Upadhyay, Isha Saxena, Soumya Pati, Shailja Singh","doi":"10.1101/2024.09.12.607918","DOIUrl":"https://doi.org/10.1101/2024.09.12.607918","url":null,"abstract":"Microglia, the residential immune cells in the central nervous system (CNS) exhibited in multiple states from resting to activated, play a significant role in neurogenesis, myelination, synaptic transmission, immune surveillance, and neuroinflammation. The aggravated inflammatory response by microglia triggers the generation of superoxide, which often causes the degeneration of neurons, leading to the development of Parkinson's and Alzheimer's. The oxidative stress is key to many neurological disorders, often regulated by many genes. The terminal neutralization of oxidative stress is mediated by NADPH and glutathione. The\u0000cytosolic NADPH level is majorly contributed by a key enzyme called glucose-6-phosphate dehydrogenase (G6PD). The deficiency of G6PD is associated with hemolytic anemia,\u0000diabetes, cardiovascular, autoimmune, and neurological disorders. Our recent study indicated that G6PD deficiency decreases cytosolic NADPH levels and alters redox homeostasis and lysosomal function in microglia. Therefore, replenishment of NADPH is crucial for targeting G6PD deficiency-mediated microglial dysfunctions. This research promotes alternate\u0000metabolic pathways by targeting the expression and activity of enzymes such as isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), which are responsible for cytoplasmic\u0000NADPH production. Metabolites like citric and malic acid supplementation promote NADPH production and reduce microglial oxidative stress. Additionally, using another group of small molecule metabolites, such as dieckol and resveratrol, enhances the expression of IDH1 and ME1 enzymes to resolve potential tissue heterogeneity. Finally, combining these metabolites supplementation increased NADPH production and restored redox homeostasis and lysosomal function in G6PD deficient microglia, indicating their further use as potential therapeutics against G6PD deficiency disorders.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Schwann Cell EP2/cAMP Nanodomain to Block Pain but not Inflammation","authors":"Romina Nassini, Lorenzo Landini, Matilde Marini, Martina Chieca, Daniel Souza Monteiro de Araujo, Marco Montini, Pasquale Pensieri, Vittorio Donato Abruzzese, Gaetano De Siena, Jin Zhang, Vincenzo De Giorgi, Antonia Romitelli, Giulia Brancolini, Raquel Tonello, Chloe J. Peach, Alessandra Mastricci, Irene Scuffi, Martina Tesi, Dane D. Jensen, Brian L. Schmidt, Nigel W. Bunnett, Francesco De Logu, Pierangelo Geppetti","doi":"10.1101/2024.09.10.612200","DOIUrl":"https://doi.org/10.1101/2024.09.10.612200","url":null,"abstract":"Analgesia by non-steroidal anti-inflammatory drugs (NSAIDs) is ascribed to inhibition of prostaglandin (PG) biosynthesis and ensuing inflammation. However, NSAIDs have life-threatening side effects, and inhibition of inflammation delays pain resolution. Decoupling the mechanisms underlying PG-evoked pain vs. protective inflammation would facilitate pain treatment. Herein, we reveal that selective silencing of the PGE2 EP2 receptor in Schwann cells via an adeno-associated viral vector abrogates the indomethacin-sensitive component of pain-like responses in mice elicited by inflammatory stimuli without affecting inflammation. In human Schwann cells and in mice, EP2 activation and optogenetic stimulation of adenylyl cyclase evokes a plasma membrane-compartmentalized cyclic adenosine monophosphate (cAMP) signal that, via A-kinase anchor protein-associated protein kinase A, sustains inflammatory pain-like responses, but does not delay their resolution. Thus, an unforeseen and druggable EP2 receptor in Schwann cells, via specific cAMP nanodomains, encodes PG-mediated persistent inflammatory pain but not protective inflammation.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}