Preety Panwar, Pierre Marie Andrault, Dipon Saha, Dieter Brömme
Background and Purpose
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual-action inhibitor, possessing both anti-inflammatory and anti-resorptive properties, as a novel treatment for RA.
Experimental Approach
Therapeutic efficacy and mechanisms of ectosteric (tanshinone IIA sulfonate [T06]) and active site-directed (odanacatib [ODN]) inhibitors of cathepsin K (CatK) were evaluated in RA mouse models. Pathology was assessed through biochemical analyses and histopathological examination. Flow cytometry analysis was performed to characterize immune cells. Anti-inflammatory effects of T06 on nuclear factor kappa beta (NF-κB) pathway were studied in macrophages.
Key Results
T06 effectively lowered the number of joint-resident immune cells, accompanied by significantly reduced production of inflammatory cytokines and collagenolytic proteases. This also included the suppression of Th17 cells and IL-17, resulting in the reduction of osteoclasts in arthritic joints and amplification of the overall anti-resorptive effect of T06, which has been attributed to its selective inhibition of the collagenolytic activity of CatK by preventing its oligomerization. The anti-inflammatory mechanism of T06 was based on blocking the phosphorylation of IκBα in the NF-κB pathway, resulting in reduced activation and expression of inflammatory cytokines. In contrast, ODN had no effect on inflammation and disease progression and was limited to the inhibition of CatK.
Conclusions
The combined anti-resorptive and anti-inflammatory activities characterize T06 as a novel therapeutic agent for RA.
{"title":"Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice","authors":"Preety Panwar, Pierre Marie Andrault, Dipon Saha, Dieter Brömme","doi":"10.1111/bph.17312","DOIUrl":"10.1111/bph.17312","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual-action inhibitor, possessing both anti-inflammatory and anti-resorptive properties, as a novel treatment for RA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Therapeutic efficacy and mechanisms of ectosteric (tanshinone IIA sulfonate [T06]) and active site-directed (odanacatib [ODN]) inhibitors of cathepsin K (CatK) were evaluated in RA mouse models. Pathology was assessed through biochemical analyses and histopathological examination. Flow cytometry analysis was performed to characterize immune cells. Anti-inflammatory effects of T06 on nuclear factor kappa beta (NF-κB) pathway were studied in macrophages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>T06 effectively lowered the number of joint-resident immune cells, accompanied by significantly reduced production of inflammatory cytokines and collagenolytic proteases. This also included the suppression of Th17 cells and IL-17, resulting in the reduction of osteoclasts in arthritic joints and amplification of the overall anti-resorptive effect of T06, which has been attributed to its selective inhibition of the collagenolytic activity of CatK by preventing its oligomerization. The anti-inflammatory mechanism of T06 was based on blocking the phosphorylation of IκBα in the NF-κB pathway, resulting in reduced activation and expression of inflammatory cytokines. In contrast, ODN had no effect on inflammation and disease progression and was limited to the inhibition of CatK.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The combined anti-resorptive and anti-inflammatory activities characterize T06 as a novel therapeutic agent for RA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 24","pages":"5009-5027"},"PeriodicalIF":6.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regina N. Nagy, András Makkos, Tamás Baranyai, Zoltán Giricz, Márta Szabó, Bernadett Kravcsenko-Kiss, Zoltán Bereczki, Bence Ágg, László G. Puskás, Nóra Faragó, Rainer Schulz, Mariann Gyöngyösi, Dominika Lukovic, Zoltán V. Varga, Anikó Görbe, Péter Ferdinandy
Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect.
{"title":"Cardioprotective microRNAs (protectomiRs) in a pig model of acute myocardial infarction and cardioprotection by ischaemic conditioning: MiR-450a","authors":"Regina N. Nagy, András Makkos, Tamás Baranyai, Zoltán Giricz, Márta Szabó, Bernadett Kravcsenko-Kiss, Zoltán Bereczki, Bence Ágg, László G. Puskás, Nóra Faragó, Rainer Schulz, Mariann Gyöngyösi, Dominika Lukovic, Zoltán V. Varga, Anikó Görbe, Péter Ferdinandy","doi":"10.1111/bph.17313","DOIUrl":"https://doi.org/10.1111/bph.17313","url":null,"abstract":"Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"83 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>It has been a year since we held the ‘Binding Kinetics and Mechanistic PK/PD modelling’ meeting in Cambridge. The event was a roaring success with some of the best mechanistic enzymologists and PK/PD modellers attending and presenting their work at the event. Now, it gives me immense pleasure to present to you these three reviews summarising the advances discussed at the meeting, covering the highlights and nuances of how binding kinetics has played a major role in redefining the quantification of drug–target interactions and PK/PD modelling.</p><p>For small-molecule drug discovery, binding kinetics is critical in understanding how the matrix events of small-molecule association, small-molecule dissociation (and the attendant residence time), small-molecule half-life in systemic circulation (and, as an extension, at the site of action) and the half-life of the protein target coalesce together to give us the therapeutic index and window. The latter parameters are essential to appreciate efficacy in light of toxicity (the latter could be on-target and/or off-target dependent on the affinity and kinetics of the small molecule's interaction with the target of interest versus other proteins). As we transition from small molecules to large molecules and from predominantly reversible equilibrium inhibition to other modalities such as non-equilibrium irreversible and degradation, these tenets are becoming all the more relevant in quantifying efficacy weighed against potential toxicity. The correct assessment of the concentration of a small molecule at its site of action is very important. This would depend on (1) intravascular versus extravascular administration with potential first pass depletion, (2) deciding on the strategy of administration as a single bolus dose versus infusion, (3) measuring the outcomes of diuretic effects in clearing the small molecule from systemic circulation as a function of dose concentration, (4) dose frequency and dosing mode and (5) assessing the effects of type I and type II mechanisms in metabolizing the small molecule with potential excretion; and are factors that have been traditionally considered very critical in understanding the concentration and, thus, efficacy of the action of small molecules and have been historically classed as aspects of pharmacokinetic modelling. Likewise, the equilibrium measure of affinity, signifying the potency of the small molecule's interaction with its target of interest, has been quantified by pharmacodynamic measures. These measures, in spite of their limitation in understanding the time evolution of the small molecule's interaction with their target of interest, have supported decision making for small-molecule drug discovery cascades.</p><p>However, with emergent modalities such as PROTAC (where a bivalent ligand recruits the protein of interest to an E3 ligase resulting in its ubiquitination and subsequent degradation), molecular glues (where a small molecule facilitates protein
这些综述做出了重要贡献，强调了结合动力学和机理 PK/PD 建模领域这些新兴概念在帮助药物发现决策方面的重要性，并有可能阻止药物损耗（Hill & Kilpatrick, 2023; Knockenhauer & Copeland, 2023; Liu et al.
{"title":"Advances in binding kinetics and mechanistic PK/PD modelling","authors":"Bharath Srinivasan","doi":"10.1111/bph.17340","DOIUrl":"10.1111/bph.17340","url":null,"abstract":"<p>It has been a year since we held the ‘Binding Kinetics and Mechanistic PK/PD modelling’ meeting in Cambridge. The event was a roaring success with some of the best mechanistic enzymologists and PK/PD modellers attending and presenting their work at the event. Now, it gives me immense pleasure to present to you these three reviews summarising the advances discussed at the meeting, covering the highlights and nuances of how binding kinetics has played a major role in redefining the quantification of drug–target interactions and PK/PD modelling.</p><p>For small-molecule drug discovery, binding kinetics is critical in understanding how the matrix events of small-molecule association, small-molecule dissociation (and the attendant residence time), small-molecule half-life in systemic circulation (and, as an extension, at the site of action) and the half-life of the protein target coalesce together to give us the therapeutic index and window. The latter parameters are essential to appreciate efficacy in light of toxicity (the latter could be on-target and/or off-target dependent on the affinity and kinetics of the small molecule's interaction with the target of interest versus other proteins). As we transition from small molecules to large molecules and from predominantly reversible equilibrium inhibition to other modalities such as non-equilibrium irreversible and degradation, these tenets are becoming all the more relevant in quantifying efficacy weighed against potential toxicity. The correct assessment of the concentration of a small molecule at its site of action is very important. This would depend on (1) intravascular versus extravascular administration with potential first pass depletion, (2) deciding on the strategy of administration as a single bolus dose versus infusion, (3) measuring the outcomes of diuretic effects in clearing the small molecule from systemic circulation as a function of dose concentration, (4) dose frequency and dosing mode and (5) assessing the effects of type I and type II mechanisms in metabolizing the small molecule with potential excretion; and are factors that have been traditionally considered very critical in understanding the concentration and, thus, efficacy of the action of small molecules and have been historically classed as aspects of pharmacokinetic modelling. Likewise, the equilibrium measure of affinity, signifying the potency of the small molecule's interaction with its target of interest, has been quantified by pharmacodynamic measures. These measures, in spite of their limitation in understanding the time evolution of the small molecule's interaction with their target of interest, have supported decision making for small-molecule drug discovery cascades.</p><p>However, with emergent modalities such as PROTAC (where a bivalent ligand recruits the protein of interest to an E3 ligase resulting in its ubiquitination and subsequent degradation), molecular glues (where a small molecule facilitates protein","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 21","pages":"4089-4090"},"PeriodicalIF":6.8,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Identifying and understanding the relationships between drug intake and adverse effects that can occur due to inadvertent molecular interactions between drugs and targets is a difficult task, especially considering the numerous variables that can influence the onset of such events. The ability to predict these side effects in advance would help physicians develop strategies to avoid or counteract them. In this article, we review the main computational methods for predicting side effects caused by drug molecules, highlighting their performance, limitations and application cases. Furthermore, we provide an overall view of resources, such as databases and tools, useful for building side effect prediction analyses.
{"title":"Network medicine and systems pharmacology approaches to predicting adverse drug effects","authors":"Alessio Funari, Giulia Fiscon, Paola Paci","doi":"10.1111/bph.17330","DOIUrl":"https://doi.org/10.1111/bph.17330","url":null,"abstract":"Identifying and understanding the relationships between drug intake and adverse effects that can occur due to inadvertent molecular interactions between drugs and targets is a difficult task, especially considering the numerous variables that can influence the onset of such events. The ability to predict these side effects in advance would help physicians develop strategies to avoid or counteract them. In this article, we review the main computational methods for predicting side effects caused by drug molecules, highlighting their performance, limitations and application cases. Furthermore, we provide an overall view of resources, such as databases and tools, useful for building side effect prediction analyses.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paula Morales, Magdalena M. Scharf, Marcel Bermudez, Attila Egyed, Rafael Franco, Olivia K. Hansen, Nadine Jagerovic, Jan Jakubík, György M. Keserű, Dóra Judit Kiss, Pawel Kozielewicz, Olav Larsen, Maria Majellaro, Ana Mallo‐Abreu, Gemma Navarro, Rubén Prieto‐Díaz, Mette M. Rosenkilde, Eddy Sotelo, Holger Stark, Tobias Werner, Laura M. Wingler
Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR‐biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications.
A 类 G 蛋白偶联受体（GPCR）因其在细胞信号传导中的重要作用及其作为药物靶点的重要性而持续受到关注。尽管临床上有许多药物都以这些受体为靶点，但仍有 60% 以上的 GPCR 尚待开发。此外，现有的无偏见 GPCR 调节剂所引发的不良反应也限制了它们的使用和治疗价值。在这种情况下，对偏性信号的阐明开辟了新的药理学途径，有望实现更安全的治疗。功能选择性配体有利于受体构象，从而促进特定效应物的招募和相关途径的调节。这篇综述调查了目前 GPCR 偏向调节剂的药物发现情况，重点关注最新进展。根据 A 类 GPCR 家族的不同，对这种优先耦合的生物效应的了解也处于不同阶段。因此，我们以单个 GPCR 家族为重点，对过去几年报道的功能选择性调节剂进行了汇编。在此过程中，我们剖析了它们的治疗相关性、分子决定因素和潜在的临床应用。
{"title":"Progress on the development of Class A GPCR‐biased ligands","authors":"Paula Morales, Magdalena M. Scharf, Marcel Bermudez, Attila Egyed, Rafael Franco, Olivia K. Hansen, Nadine Jagerovic, Jan Jakubík, György M. Keserű, Dóra Judit Kiss, Pawel Kozielewicz, Olav Larsen, Maria Majellaro, Ana Mallo‐Abreu, Gemma Navarro, Rubén Prieto‐Díaz, Mette M. Rosenkilde, Eddy Sotelo, Holger Stark, Tobias Werner, Laura M. Wingler","doi":"10.1111/bph.17301","DOIUrl":"https://doi.org/10.1111/bph.17301","url":null,"abstract":"Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR‐biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"61 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gerald Wölkart, Simon Gissing, Heike Stessel, Erin K. Fassett, Burkhard Klösch, Robert W. Greene, Bernd Mayer, John T. Fassett
Background and Purpose
Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia–reperfusion (IR) injury (24–72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection.
Experimental Approach
Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24–120 h later. Theophylline or bortezomib was administered 24 h after ABT-702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac-specific ADK KO (cADK+/−) mice. Cardiac ADK expression was also examined after A1 or A3 receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration.
Key results
ABT-702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96–120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT-702-induced ADK protein deficit and cardioprotection at 72 h. cADK+/− hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression.
Conclusion and Implications
A positive feedback loop driven by adenosine receptor-induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT-702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK+/− hearts.
{"title":"An adenosinergic positive feedback loop extends pharmacological cardioprotection duration","authors":"Gerald Wölkart, Simon Gissing, Heike Stessel, Erin K. Fassett, Burkhard Klösch, Robert W. Greene, Bernd Mayer, John T. Fassett","doi":"10.1111/bph.17331","DOIUrl":"10.1111/bph.17331","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia–reperfusion (IR) injury (24–72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24–120 h later. Theophylline or bortezomib was administered 24 h after ABT-702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac-specific ADK KO (cADK<sup>+/−</sup>) mice. Cardiac ADK expression was also examined after A<sub>1</sub> or A<sub>3</sub> receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>ABT-702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96–120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT-702-induced ADK protein deficit and cardioprotection at 72 h. cADK<sup>+/−</sup> hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>A positive feedback loop driven by adenosine receptor-induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT-702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK<sup>+/−</sup> hearts.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4920-4936"},"PeriodicalIF":6.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17331","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura Latini, Daniel Souza Monteiro De Araujo, Rosario Amato, Alessio Canovai, Lucia Buccarello, Francesco De Logu, Elena Novelli, Anastasiia Vlasiuk, Francesca Malerba, Ivan Arisi, Rita Florio, Hiroki Asari, Simona Capsoni, Enrica Strettoi, Gino Villetti, Bruno Pietro Imbimbo, Massimo Dal Monte, Romina Nassini, Pierangelo Geppetti, Silvia Marinelli, Antonino Cattaneo
Background and Purpose
Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).
Experimental Approach
Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.
Results
hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.
Conclusions and Implications
Our data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.
{"title":"A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia","authors":"Laura Latini, Daniel Souza Monteiro De Araujo, Rosario Amato, Alessio Canovai, Lucia Buccarello, Francesco De Logu, Elena Novelli, Anastasiia Vlasiuk, Francesca Malerba, Ivan Arisi, Rita Florio, Hiroki Asari, Simona Capsoni, Enrica Strettoi, Gino Villetti, Bruno Pietro Imbimbo, Massimo Dal Monte, Romina Nassini, Pierangelo Geppetti, Silvia Marinelli, Antonino Cattaneo","doi":"10.1111/bph.17316","DOIUrl":"10.1111/bph.17316","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Our data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4890-4919"},"PeriodicalIF":6.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear.
Experimental approach
The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain.
Key Results
60 min after injection, ketamine (10 mg·kg−1, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg−1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice.
Conclusion and Implications
This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.
{"title":"Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine","authors":"Yong-Yu Yin, Jiao-Zhao Yan, Qian-Qian Wei, Si-Rui Sun, Yu-Qiang Ding, Li-Ming Zhang, Yun-Feng Li","doi":"10.1111/bph.17324","DOIUrl":"10.1111/bph.17324","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. <i>Tph2</i> knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>60 min after injection, ketamine (10 mg·kg<sup>−1</sup>, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by <i>Tph2</i> knockout. Importantly, NBQX (10 mg·kg<sup>−1</sup>, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4874-4889"},"PeriodicalIF":6.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elisa Bellantoni, Matilde Marini, Martina Chieca, Chiara Gabellini, Erica Lucia Crapanzano, Daniel Souza Monteiro de Araujo, Daniele Nosi, Lorenzo Roschi, Lorenzo Landini, Gaetano De Siena, Pasquale Pensieri, Alessandra Mastricci, Irene Scuffi, Pierangelo Geppetti, Romina Nassini, Francesco De Logu
Background and Purpose
The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro-algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy-induced peripheral neuropathy (CIPN) in zebrafish larvae.
Experimental Approach
We used zebrafish larvae and a mouse model to test oxaliplatin-evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin-induced CIPN model.
Key Results
We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)-transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co-expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (Plp1+-Trpa1 mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin-evoked nociceptive behaviours.
Conclusion and Implications
These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro-allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom.
{"title":"Schwann cell transient receptor potential ankyrin 1 (TRPA1) ortholog in zebrafish larvae mediates chemotherapy-induced peripheral neuropathy","authors":"Elisa Bellantoni, Matilde Marini, Martina Chieca, Chiara Gabellini, Erica Lucia Crapanzano, Daniel Souza Monteiro de Araujo, Daniele Nosi, Lorenzo Roschi, Lorenzo Landini, Gaetano De Siena, Pasquale Pensieri, Alessandra Mastricci, Irene Scuffi, Pierangelo Geppetti, Romina Nassini, Francesco De Logu","doi":"10.1111/bph.17318","DOIUrl":"10.1111/bph.17318","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro-algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy-induced peripheral neuropathy (CIPN) in zebrafish larvae.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We used zebrafish larvae and a mouse model to test oxaliplatin-evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin-induced CIPN model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)-transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co-expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (<i>Plp1</i><sup>+</sup><i>-Trpa1</i> mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin-evoked nociceptive behaviours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro-allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4859-4873"},"PeriodicalIF":6.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yahan Liu, Zhipeng Wang, Li Fang, Yaohua Xu, Beilei Zhao, Xuya Kang, Yanqing Zhao, Jintao Han, Yan Zhang, Erdan Dong, Nanping Wang
Background and purpose: Elevated levels of 5-HT have been correlated with coronary artery disease and cardiac events, suggesting 5-HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5-HT system in atherosclerosis remain unclear. The 5-HT2B receptor (5-HT2BR), which establishes a positive feedback loop with 5-HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5-HT2BR in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice.
Experimental approach: Plasma levels of 5-HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE-/- mice by employing both pharmacological inhibition and genetic deficiency of 5-HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5-HT2BR-deficient mice.
Key results: An upregulation of 5-HT2BR expression was observed in the aortas of ApoE-/- mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5-HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5-HT2BR-deficient cells. 5-HT2BR-deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin-1β release. Moreover, macrophages primed with 5-HT2BR deficiency displayed an anti-inflammatory phenotype.
Conclusion and implications: These findings support the hypothesis that 5-HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis-related diseases.
{"title":"Deficiency of 5-HT<sub>2B</sub> receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling.","authors":"Yahan Liu, Zhipeng Wang, Li Fang, Yaohua Xu, Beilei Zhao, Xuya Kang, Yanqing Zhao, Jintao Han, Yan Zhang, Erdan Dong, Nanping Wang","doi":"10.1111/bph.17315","DOIUrl":"https://doi.org/10.1111/bph.17315","url":null,"abstract":"<p><strong>Background and purpose: </strong>Elevated levels of 5-HT have been correlated with coronary artery disease and cardiac events, suggesting 5-HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5-HT system in atherosclerosis remain unclear. The 5-HT<sub>2B</sub> receptor (5-HT2BR), which establishes a positive feedback loop with 5-HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5-HT2BR in atherosclerosis-prone apolipoprotein E-deficient (ApoE<sup>-/-</sup>) mice.</p><p><strong>Experimental approach: </strong>Plasma levels of 5-HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE<sup>-/-</sup> mice by employing both pharmacological inhibition and genetic deficiency of 5-HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5-HT2BR-deficient mice.</p><p><strong>Key results: </strong>An upregulation of 5-HT2BR expression was observed in the aortas of ApoE<sup>-/-</sup> mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5-HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5-HT2BR-deficient cells. 5-HT2BR-deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin-1β release. Moreover, macrophages primed with 5-HT2BR deficiency displayed an anti-inflammatory phenotype.</p><p><strong>Conclusion and implications: </strong>These findings support the hypothesis that 5-HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis-related diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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