Pharmacological research最新文献

{"title":"Kallikrein inhibitor derived from immunoglobulin heavy chain junction region possesses anti-thromboinflammation potential","authors":"Juan Yang ,&nbsp;Ziyu Li ,&nbsp;Xinyi Deng ,&nbsp;Mengru Li ,&nbsp;Bin Li ,&nbsp;Rebecca Caroline Thuku ,&nbsp;Qian Chen ,&nbsp;Xiang Sun ,&nbsp;Qiumin Lu ,&nbsp;Mingqian Fang","doi":"10.1016/j.phrs.2024.107460","DOIUrl":"10.1016/j.phrs.2024.107460","url":null,"abstract":"<div><div>Influenza vaccination is associated with a reduced incidence of cardiovascular events, cardiovascular death, and all-cause mortality. However, the functional role of the associated immunoglobulin remains unclear. This study identified a specific influenza-related immunoglobulin heavy chain junction region sequence (Ser-Leu-Gly-Ala-Ser-Asp, SD6) that inhibited plasma kallikrein (PKa) activity to resist thromboinflammatory responses and stroke injury. PKa is considered an attractive therapeutic target for alleviating the complications of thrombophilia-induced inflammation. <em>In vitro</em>, SD6 prolonged plasma recalcification and activated partial thromboplastin time, with no effects on bleeding risk-related prothrombin time, indicating selective inhibition of the intrinsic coagulation pathway. Correspondingly, at doses ranging from 0.25 to 4 mg/kg, SD6 attenuated arterial and cortical venous thrombosis in FeCl₃-induced and photochemically induced mice, without impacting hemorrhage risk, and further mitigated cerebral inflammatory injury in a mouse model of transient middle cerebral artery occlusion ischemic stroke. These findings suggest that SD6 may serve as a potential therapeutic agent for the treatment of thromboinflammatory conditions.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107460"},"PeriodicalIF":9.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406692","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}

{"title":"Novel deoxyhypusine synthase (DHPS) inhibitors target hypusination-induced vasculogenic mimicry (VM) against malignant melanoma","authors":"Xi-he Zhao ,&nbsp;Jian Ma ,&nbsp;Jing-si Guo ,&nbsp;Kai-li Liu ,&nbsp;Yu-xi Qin ,&nbsp;Long-tian Li ,&nbsp;Ji-fang Zhang ,&nbsp;Yue-ying Yang ,&nbsp;Shi-chen Zhang ,&nbsp;Fan-hao Meng ,&nbsp;Lei Liu ,&nbsp;Yue-hui Yang ,&nbsp;Xin-yang Li","doi":"10.1016/j.phrs.2024.107453","DOIUrl":"10.1016/j.phrs.2024.107453","url":null,"abstract":"<div><div>Vasculogenic mimicry (VM) contributes factor to the poor prognosis of malignant melanoma. Developing deoxyhypusine synthase (DHPS) inhibitors against melanoma VM is clinically essential. In this study, we optimized and synthesized a series of compounds based on the candidate structure, and the hit compound <strong>7k</strong> was identified through enzyme assay and cell viability inhibition screening. Both inside and outside the cell, <strong>7k</strong>'s ability to target DHPS and its high affinity were demonstrated. Molecular dynamics and point mutation indicated that mutations of K329 or V129 in DHPS abolish <strong>7k</strong>'s inhibitory activity. Using PCR arrays, solid-state antibody microarrays, and angiogenesis assays investigated <strong>7k</strong>'s impact on melanoma cells to reveal that DHPS regulates melanoma VM by promoting FGFR2 and c-KIT expression. Surprisingly, <strong>7k</strong> was discovered to inhibit MC1R-mediated melanin synthesis in the zebrafish. Pharmacokinetic evaluations demonstrated <strong>7k</strong>'s favorable properties, and xenograft models evidenced its notable anti-melanoma efficacy, achieving a TGI of 73 %. These results highlighted DHPS as key in melanoma VM formation and confirmed <strong>7k</strong>'s potential as a novel anti-melanoma agent.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107453"},"PeriodicalIF":9.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406693","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}

{"title":"Regulation of microglia inflammation and oligodendrocyte demyelination by Engeletin via the TLR4/RRP9/NF-κB pathway after spinal cord injury","authors":"Wang Chen ,&nbsp;Leshu Zhang ,&nbsp;Guangdi Zhong ,&nbsp;Shuang Liu ,&nbsp;Yuxuan Sun ,&nbsp;Jiayun Zhang ,&nbsp;Zehan Liu ,&nbsp;Lichun Wang","doi":"10.1016/j.phrs.2024.107448","DOIUrl":"10.1016/j.phrs.2024.107448","url":null,"abstract":"<div><div>Microglia polarization is crucial for neuroinflammatory response after spinal cord injury (SCI). Small molecule compounds and hub genes play an important role in regulating microglia polarization, reducing neuroinflammatory response and oligodendrocyte demyelination after SCI. In this study, suitable data sets were used to screen hub genes, and Western blot and Immunofluorescence (IF) experiments were used to confirm the expressions of proteins related to SDAD1, RRP9 and NF-κB pathways under LPS/SCI conditions. Engeletin (ENG) reduced microglia polarization and inflammation in vivo and in vitro via the SDAD1, RRP9 or NF-κB signaling pathways. In addition, ENG binds to the membrane receptor Toll-like receptor 4 (TLR4) through small molecule-protein docking. COIP experiment and protein-protein docking revealed protein-protein interaction (PPI) between RRP9 and SDAD1. By gene knock-down (KD) / overexpression (OE) and Western blot experiments, RRP9 and SDAD1 can regulate inflammatory response through NF-κB signaling and ribosome biogenesis pathway. Western blot analysis showed that CU increased the expression of SDAD1, RRP9 and NF-κB pathway related proteins through TLR1/2, while C34 decreased the expression of SDAD1 and RRP9 proteins through TLR4. These results suggest that ENG can reduce inflammation through TLR4/RRP9(SDAD1)/NF-κB signaling pathway. In addition, we demonstrated that oligodendrocyte apoptosis and demyelination could be influenced by the regulation of microglia and tissue inflammation. In conclusion, this study found the gene Rrp9/Sdad1 and the small molecule compound ENG, which control the inflammatory response of microglia, and further explored the related mechanism of oligodendrocyte demyelination, which has important theoretical significance.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107448"},"PeriodicalIF":9.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433401","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}

{"title":"New therapeutic avenues in multiple sclerosis: Is there a place for gut microbiota-based treatments?","authors":"Lucrezia Irene Maria Campagnoli ,&nbsp;Nicoletta Marchesi ,&nbsp;Angelica Varesi ,&nbsp;Martina Morozzi ,&nbsp;Linda Mascione ,&nbsp;Giovanni Ricevuti ,&nbsp;Ciro Esposito ,&nbsp;Nicoletta Galeotti ,&nbsp;Alessia Pascale","doi":"10.1016/j.phrs.2024.107456","DOIUrl":"10.1016/j.phrs.2024.107456","url":null,"abstract":"<div><div>The bidirectional interaction between the gut and the central nervous system (CNS), the so-called gut microbiota-brain axis, is reported to influence brain functions, thus having a potential impact on the development or the progression of several neurodegenerative disorders. Within this context, it has been documented that multiple sclerosis (MS), an autoimmune inflammatory, demyelinating, and neurodegenerative disease of the CNS, is associated with gastrointestinal symptoms, including constipation, dysphagia, and faecal incontinence. Moreover, some evidence suggests the existence of an altered gut microbiota (GM) composition in MS patients with respect to healthy individuals, as well as the potential influence of GM dysbiosis on typical MS features, including increased intestinal permeability, disruption of blood-brain barrier integrity, chronic inflammation, and altered T cells differentiation. Starting from these assumptions, the possible involvement of GM alteration in MS pathogenesis seems likely, and its restoration could represent a supplemental beneficial strategy against this disabling disease. In this regard, the present review will explore possible preventive approaches (including several dietary interventions, the administration of probiotics, prebiotics, synbiotics, and postbiotics, and the use of faecal microbiota transplantation) to be pursued as prophylaxis or in combination with pharmacological treatments with the aim of re-establishing a proper GM, thus helping to prevent the development of this disease or to manage it by alleviating symptoms or slowing down its progression.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107456"},"PeriodicalIF":9.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400953","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}

{"title":"Flavonoids and their derivatives as DNA topoisomerase inhibitors with anti-cancer activity in various cell models: Exploring a novel mode of action","authors":"Przemysław Sitarek ,&nbsp;Anna Merecz-Sadowska ,&nbsp;Joanna Sikora ,&nbsp;Malwina Dudzic ,&nbsp;Natasza Wiertek-Płoszaj ,&nbsp;Laurent Picot ,&nbsp;Tomasz Śliwiński ,&nbsp;Tomasz Kowalczyk","doi":"10.1016/j.phrs.2024.107457","DOIUrl":"10.1016/j.phrs.2024.107457","url":null,"abstract":"<div><div>Flavonoids, a diverse group of plant-derived secondary metabolites, have garnered significant attention for their potential anti-cancer properties. This review explores the role of flavonoids as inhibitors of DNA topoisomerases, key enzymes essential for DNA replication, transcription, and cell division. The article offers a comprehensive overview of flavonoid classification, biosynthesis, and their widespread natural occurrence. It further delves into the molecular mechanisms through which flavonoids exert their anti-cancer effects, emphasizing their interactions with topoisomerases. The review provides a thorough analysis of both in vitro and <em>in vivo</em> studies that highlight the topoisomerase inhibitory activities of various flavonoids and their derivatives. Key findings demonstrate that flavonoids can function as catalytic inhibitors, poisons, or DNA intercalators, affecting both type I and type II topoisomerases. The structure-activity relationships of flavonoids concerning their topoisomerase inhibitory potency are also examined. This review underscores the potential of flavonoids as promising lead compounds for the development of novel topoisomerase inhibitors, which could have important implications for cancer therapy. However, it also acknowledges the need for further research to fully understand the intricate interactions between flavonoids and topoisomerases within the cellular environment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107457"},"PeriodicalIF":9.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400951","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}

{"title":"Flavonoids, gut microbiota and cardiovascular disease: Dynamics and interplay","authors":"Hadi Mansour ,&nbsp;Hasan Slika ,&nbsp;Suzanne A. Nasser ,&nbsp;Gianfranco Pintus ,&nbsp;Maha Khachab ,&nbsp;Amirhossein Sahebkar ,&nbsp;Ali H. Eid","doi":"10.1016/j.phrs.2024.107452","DOIUrl":"10.1016/j.phrs.2024.107452","url":null,"abstract":"<div><div>Cardiovascular disease (CVD) remains the leading cause of global morbidity and mortality. Extensive efforts have been invested to explicate mechanisms implicated in the onset and progression of CVD. Besides the usual suspects as risk factors (obesity, diabetes, and others), the gut microbiome has emerged as a prominent and essential factor in the pathogenesis of CVD. With its endocrine-like effects, the microbiome modulates many physiologic processes. As such, it is not surprising that dysbiosis-by generating metabolites, inciting inflammation, and altering secondary bile acid signaling- could predispose to or aggravate CVD. Nevertheless, various natural and synthetic compounds have been shown to modulate the microbiome. Prime among these molecules are flavonoids, which are natural polyphenols mainly present in fruits and vegetables. Accumulating evidence supports the potential of flavonoids in attenuating the development of CVD. The ascribed mechanisms of these compounds appear to involve mitigation of inflammation, alteration of the microbiome composition, enhancement of barrier integrity, induction of reverse cholesterol transport, and activation of farnesoid X receptor signaling. In this review, we critically appraise the methods by which the gut microbiome, despite being essential to the human body, predisposes to CVD. Moreover, we dissect the mechanisms and pathways underlying the cardioprotective effects of flavonoids.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107452"},"PeriodicalIF":9.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392393","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}

{"title":"Profiling the impact of anti-human CD20 monoclonal antibodies on lymphocyte B cell subsets and their precursors in the bone marrow and in lymphoid tissues in an immunocompromised mouse engrafted with human cells","authors":"Annalisa Moregola ,&nbsp;Fabrizia Bonacina ,&nbsp;Giovanni Battista Vingiani ,&nbsp;Roberta Frapolli ,&nbsp;Renato Turrini ,&nbsp;Giuseppe Danilo Norata","doi":"10.1016/j.phrs.2024.107442","DOIUrl":"10.1016/j.phrs.2024.107442","url":null,"abstract":"<div><div>Ofatumumab (OFA) and ocrelizumab (OCRE) are two anti-CD20 monoclonal antibodies approved for the treatment of relapsing forms of multiple sclerosis due to their ability to deplete B lymphocytes. The aim of this study was to investigate the impact of these anti-hCD20 antibodies on B lymphocyte subsets in the circulation and in primary and secondary lymphoid organs in an immune system humanized mouse model (immunocompromised Rag2^−/−Il2rg^−/−CD47^−/−) engrafted with human CD34+ hematopoietic stem cells. Three months after humanization, mice, which present adaptive immune cells only of human origin, were treated with OFA (0.3 mg/Kg; day 1, 3 and 5), or OCRE (10 mg/kg; day 1) or saline. Seven days after the last injection a robust (&gt;90 %) decrease of circulating human CD20+ B lymphocytes was observed in both OFA- and OCRE-treated mice. A partial replenishment of B lymphocytes was detectable in blood 36 days from the last injection in OFA-treated mice, while no B lymphocytes could be detected in OCRE-treated mice up to 65 days post injection. Bone marrow profiling showed that during hCD20+ B cell depletion and replenishment, OCRE-treated mice preserved only preB-I cells in the bone marrow, while the bone marrow of OFA-treated mice presented both preB-I as well as preB-II cells, with the latter subset being the one closest to differentiate into immature B cells. These data together with changes in B cell distribution in other tissues suggest that ofatumumab preserve BM niches, critical for B lymphocyte replenishment, limiting potential side effects of the treatment associated with the increased risk of infection.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107442"},"PeriodicalIF":9.1,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392392","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}

{"title":"Cardiomyocyte-derived C-type natriuretic peptide diminishes myocardial ischaemic injury by promoting revascularisation and limiting fibrotic burden","authors":"Vanessa J. Lowe ,&nbsp;Aisah A. Aubdool ,&nbsp;Amie J. Moyes ,&nbsp;Joshua P. Dignam ,&nbsp;C. Perez-Ternero ,&nbsp;Reshma S. Baliga ,&nbsp;Nicola Smart ,&nbsp;Adrian J. Hobbs","doi":"10.1016/j.phrs.2024.107447","DOIUrl":"10.1016/j.phrs.2024.107447","url":null,"abstract":"<div><h3>Background</h3><div>C-type natriuretic peptide (CNP) is a significant player in the maintenance of cardiac and vascular homeostasis regulating local blood flow, platelet and leukocyte activation, heart structure and function, angiogenesis and metabolic balance. Since such processes are perturbed in myocardial infarction (MI), we explored the role of cardiomyocyte-derived CNP, and pharmacological administration of the peptide, in offsetting the pathological consequences of MI.</div></div><div><h3>Methods</h3><div>Wild type (WT) and cardiomyocyte-restricted CNP null (cmCNP^-/-) mice were subjected to left anterior descending coronary artery (LADCA) ligation and acute effects on infarct size and longer-term outcomes of cardiac repair explored. Heart structure and function were assessed by combined echocardiographic and molecular analyses. Pharmacological administration of CNP (0.2 mg/kg/day; s.c.) was utilized to assess therapeutic potential.</div></div><div><h3>Results</h3><div>Compared to WT littermates, cmCNP^-/- mice had a modestly increased infarct size following LADCA ligation but without significant deterioration of cardiac structural and functional indices. However, cmCNP^-/- animals exhibited overtly worse heart morphology and contractility 6 weeks following MI, with particularly deleterious reductions in left ventricular ejection fraction, dilatation, fibrosis and revascularization. This phenotype was largely recapitulated in animals with global deletion of natriuretic peptide receptor (NPR)-C (NPR-C^-/-). Pharmacological administration of CNP rescued the deleterious pathology in WT and cmCNP^-/-, but not NPR-C^-/-, animals.</div></div><div><h3>Conclusions and implications</h3><div>Cardiomyocytes synthesize and release CNP as an intrinsic protective mechanism in response to MI that reduces cardiac structural and functional deficits; these salutary actions are primarily NPR-C-dependent. Pharmacological targeting of CNP may represent a new therapeutic option for MI.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107447"},"PeriodicalIF":9.1,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392390","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}

{"title":"Antifungal properties of abnormal cannabinoid derivatives: Disruption of biofilm formation and gene expression in Candida species","authors":"Prince Ofori ,&nbsp;Natalia Zemliana ,&nbsp;Ilan Zaffran ,&nbsp;Tatiana Etzion ,&nbsp;Ronit Vogt Sionov ,&nbsp;Doron Steinberg ,&nbsp;Raphael Mechoulam ,&nbsp;Natalya M. Kogan ,&nbsp;Francesca Levi-Schaffer","doi":"10.1016/j.phrs.2024.107441","DOIUrl":"10.1016/j.phrs.2024.107441","url":null,"abstract":"<div><div>Abnormal cannabinoids (including comp 3) are a class of synthetic lipid compounds with non-psychoactive properties and regioisomer configurations, but distinct from traditional cannabinoids since they do not interact with the established CB1 and CB2 receptors. Previous research showed the cardioprotective and anti-inflammatory potentials of comp 3 and more recently its antimicrobial effect on methicillin-resistant <em>Staphylococcus aureus</em> (MRSA). Given the escalating challenges posed by <em>Candida</em> infections and the rise of antifungal drug resistance, the exploration of novel therapeutic avenues is crucial. This study aimed to assess the anti-<em>Candida</em> properties of newly synthesized AbnCBD derivatives. AbnCBD derivatives were synthesized by acid catalysis-induced coupling and further derivatized. We evaluated the potential of the AbnCBD derivatives to inhibit the growth stages of various <em>Candida</em> species. By <em>in vitro</em> colorimetric assays and <em>in vivo</em> mice experiments, we have shown that AbnCBD derivatives induce differential inhibition of <em>Candida</em> growth. The AbnCBD derivatives, especially comp 3, comp 10, and comp 9 significantly reduced the growth of <em>C. albicans</em>, including FLC-resistant strains, and of <em>C. tropicalis</em> and <em>C. parapsilosis</em> but not of <em>C auris</em> compared to their controls (FLC and 0.5 % DMSO). Comp 3 also disrupted <em>C. albicans</em> biofilm formation and eradicated mature biofilms. Notably, other derivatives of AbnCBD disrupted the biofilm formation and maturation of <em>C. albicans</em> but did not affect yeast growth. In a murine model of VVC, comp 3 demonstrated significant fungal clearance and reduced <em>C. albicans</em> burden compared to vehicle and FLC controls. These findings highlight the potential of AbnCBDs as promising antifungal agents against <em>Candida</em> infections.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107441"},"PeriodicalIF":9.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378167","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}

{"title":"β-amyloid’s neurotoxic mechanisms as defined by in vitro microelectrode arrays: a review","authors":"Aoife O’Connell ,&nbsp;Leo Quinlan ,&nbsp;Andrea Kwakowsky","doi":"10.1016/j.phrs.2024.107436","DOIUrl":"10.1016/j.phrs.2024.107436","url":null,"abstract":"<div><div>Alzheimer's disease is characterized by the aggregation of β-amyloid, a pathological feature believed to drive the neuronal loss and cognitive decline commonly seen in the disease. Given the growing prevalence of this progressive neurodegenerative disease, understanding the exact mechanisms underlying this process has become a top priority. Microelectrode arrays are commonly used for chronic, non-invasive recording of both spontaneous and evoked neuronal activity from diverse <em>in vitro</em> disease models and to evaluate therapeutic or toxic compounds. To date, microelectrode arrays have been used to investigate β-amyloids’ toxic effects, β-amyloids role in specific pathological features and to assess pharmacological approaches to treat Alzheimer’s disease. The versatility of microelectrode arrays means these studies use a variety of methods and investigate different disease models and brain regions. This review provides an overview of these studies, highlighting their disparities and presenting the status of the current literature. Despite methodological differences, the current literature indicates that β-amyloid has an inhibitory effect on synaptic plasticity and induces network connectivity disruptions. β-amyloid’s effect on spontaneous neuronal activity appears more complex. Overall, the literature corroborates the theory that β-amyloid induces neurotoxicity, having a progressive deleterious effect on neuronal signaling and plasticity. These studies also confirm that microelectrode arrays are valuable tools for investigating β-amyloid pathology from a functional perspective, helping to bridge the gap between cellular and network pathology and disease symptoms. The use of microelectrode arrays provides a functional insight into Alzheimer’s disease pathology which will aid in the development of novel therapeutic interventions.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107436"},"PeriodicalIF":9.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381406","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}