Pharmacological Reports最新文献

{"title":"Novel fluorinated cannabinoid analogs modulate cytokine expression in human C20 microglial cells.","authors":"Randall L Davis, Sascha Grotjahn, Burkhard Koenig, Daniel J Buck, Jimmie D Weaver","doi":"10.1007/s43440-024-00680-8","DOIUrl":"10.1007/s43440-024-00680-8","url":null,"abstract":"<p><strong>Background: </strong>Phytochemicals derived from the plant Cannabis sativa hold promise in terms of medicinal value. Cannabinoids such as Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are arguably the best characterized and known to possess wide-ranging therapeutic benefits. The mechanism of action for these therapeutic effects remains to be fully elucidated, however, the anti-inflammatory actions are of particular interest. Maximizing therapeutic effects while limiting adverse effects is crucial in pharmaceutical development. Fluorination of natural products often yields molecules with enhanced biological properties and provides opportunities for intellectual property protection not available to the natural product.</p><p><strong>Methods: </strong>Herein, we describe four novel cannabinoids (a deoxy trifluoroCBN analog (F₃CBN), the racemic cis-deoxy-trifluoro-THC (F₃THC), and truncated pyridine analogs of an intermediate in route to the THC and CBN, SG126 and SG154. Importantly, we provide the initial assessment of the biologic activity of these molecules, by investigating the in vitro effects on metabolic activity (via 3-[4,5-dimethylthiazol-2-yl]-2,5,-diphenyltetrazolium bromide, MTT assay) and cytokine expression (via enzyme linked immunosorbent assay, ELISA) in human C20 microglial cells.</p><p><strong>Results: </strong>The cannabinoids examined had minimal to no effect on metabolic activity up to 10 µM. Notably, F₃CBN and F₃THC potentiated interleukin-1 β (IL-1β)-induced expression of interferon-γ inducible protein 10 (CXCL10) and IL-6 expression whereas, SG126 and SG154 were inhibitory.</p><p><strong>Conclusions: </strong>These findings are foundational for new lines of investigation into the therapeutic potential of four novel fluorinated cannabinoids.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"295-301"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of statin therapy on CD40:CD40L signaling: mechanistic insights and therapeutic opportunities.","authors":"Fatemeh Askarizadeh, Sercan Karav, Tannaz Jamialahmadi, Amirhossein Sahebkar","doi":"10.1007/s43440-024-00678-2","DOIUrl":"10.1007/s43440-024-00678-2","url":null,"abstract":"<p><p>Statins are widely utilized to reduce cholesterol levels, particularly in cardiovascular diseases. They interface with cholesterol synthesis by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase enzyme. Besides their primary effect, statins demonstrate anti-inflammatory and immune-modulating properties in various diseases, highlighting the pleiotropic effect of these drugs. The CD40:CD40L signaling pathway is considered a prominent inflammatory pathway in multiple diseases, including autoimmune, inflammatory, and cardiovascular diseases. The findings from clinical trials and in vitro and in vivo studies suggest the potential anti-inflammatory effect of statins in modulating the CD40 signaling pathway and downstream inflammatory mediator. Accordingly, as its classic ligand, statins can suppress immune responses in autoimmune diseases by inhibiting CD40 expression and blocking its interaction with CD40L. Additionally, statins affect intracellular signaling and inhibit inflammatory mediator secretion in chronic inflammatory diseases like asthma and autoimmune disorders such as myasthenia gravis, multiple sclerosis, systemic lupus erymanthus, and cardiovascular diseases like atherosclerosis. However, it is essential to note that the anti-inflammatory effect of statins may vary depending on the specific type of statin used. In this study, we aim to explore the potential anti-inflammatory effects of statins in treating inflammatory diseases by examining their role in regulating immune responses, particularly their impact on the CD40:CD40L signaling pathway, through a comprehensive review of existing literature.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"43-71"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced pharmacological and pharmacokinetic evaluation of 1,3 dimethylpurine-2,6-dione derivative (GR-14) with prominent mood-modulating activity in rats.","authors":"Agnieszka Cios, Grażyna Chłoń-Rzepa, Magdalena Jastrzębska-Więsek, Krzysztof Pociecha, Katarzyna Wójcik-Pszczoła, Elżbieta Pękala, Anna Wesołowska","doi":"10.1007/s43440-024-00686-2","DOIUrl":"10.1007/s43440-024-00686-2","url":null,"abstract":"<p><strong>Background: </strong>Research on new candidates for antidepressant/anxiolytic drugs from the long-chain arylpiperazines (LCAPs) group containing a 1,3-dimethylpurine-2,6-dione as a terminal amide fragment fits into the modern exploration trend. This study aimed to examine, for the first time in male Wistar rats, pharmacodynamic (antidepressant- and anxiolytic-like) and pharmacokinetic properties of 7-(5-(4-(3-chlorophenyl)piperazin-1-yl)pentyl)-1,3-dimethyl-3,7-dihydro-1 H-purine-2,6-dione hydrochloride (GR-14).</p><p><strong>Methods: </strong>Antidepressant- and anxiolytic-like activities have been assessed in the forced swim test (FST) and Vogel conflict drinking test, respectively. The pharmacokinetic characteristics of GR-14, its distribution into rat tissues, and several in vitro ADME-Tox parameters (hepatocytotoxic, neurocytotoxic, metabolic stability) have been defined.</p><p><strong>Results: </strong>GR-14 produces strong and dose-dependent antidepressant- and anxiolytic-like effects in both tests used. Pharmacokinetic findings demonstrate that GR-14 reveals linear pharmacokinetics tested after intravenous (iv) and was rapidly absorbed after oral (po) administration. It rapidly crosses the blood-brain barrier (BBB) which is vital for therapeutic effects in vivo in psychiatric diseases, depression, and anxiety. Moreover, it is slowly eliminated from the brain, maintaining concentrations higher than those in plasma at the last time point measured. Further studies have also shown that GR-14 is an average high-clearance drug in rat liver microsomes and exerts neither hepatocytotoxic nor neurocytotoxic effects in vitro.</p><p><strong>Conclusion: </strong>The tested derivative GR-14 presents prominent mood-modulating activity in rats and has promising pharmacokinetic parameters and a good safety profile. The beneficial pharmacology and pharmacokinetics of GR-14 in vivo are in high concordance with its profile in vitro, thus underlining very hopeful properties to support the early development process.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"158-171"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety of dapagliflozin and empagliflozin in cases with diabetes mellitus or/and heart failure: a retrospective pharmacovigilance study conducted on the eudravigilance database.","authors":"Annamaria Mascolo, Alessia Zinzi, Mario Gaio, Donatella Ruggiero, Cristina Scavone, Francesco Rossi, Annalisa Capuano","doi":"10.1007/s43440-024-00668-4","DOIUrl":"10.1007/s43440-024-00668-4","url":null,"abstract":"<p><strong>Introduction: </strong>Dapagliflozin and empagliflozin are sodium-glucose cotransporter-2 (SGLT2) inhibitors initially approved for the treatment of type 2 diabetes mellitus (DM), and later for heart failure (HF). Considering this differential therapeutic use, we decided to evaluate cases related to these agents by comparing those with DM, HF, or both (DM and HF).</p><p><strong>Methods: </strong>A retrospective, pharmacovigilance study was conducted by using data contained in the EudraVigilance from January 1st, 2021, to December 31st, 2023. Cases were classified into those with DM, HF, or both diseases. The Reporting Odds Ratio (ROR), and its 95% confidence interval (95%CI) were computed to compare the reporting probability of the four most reported adverse events. The following comparisons were performed: DM vs. HF; both DM and HF vs. HF; both DM and HF vs. DM. Analyses were adjusted for age, sex, and time between the approval date of the SGLT2 inhibitor and the reporting date.</p><p><strong>Results: </strong>A total of 14,594 (50.5%) cases were classifiable for DM (N = 11,962; 82.0%), HF (N = 2,100; 14.4%), or both DM and HF (N = 532; 3.64%). The empagliflozin was the most reported SGLT2 inhibitor (60.1%), and only 15 cases (0.1%) reported both empagliflozin and dapagliflozin. Cases with DM and both DM and HF were associated with a higher reporting probability of ketoacidosis (ROR: 5.95, 95%CI: 4.87-7.26; ROR: 3.05, 95%CI: 2.27-4.09) and Fournier's gangrene (ROR: 2.30, 95%CI: 1.65-3.20; ROR: 2.30, 95%CI: 1.38-3.82) than HF. These results were also confirmed by adjusted analyses.</p><p><strong>Conclusion: </strong>We found that ketoacidosis and Fournier's gangrene had a higher reporting in cases with DM. Further studies are warranted.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"274-286"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"c-Myc inhibition and p21 modulation contribute to unsymmetrical bisacridines-induced apoptosis and senescence in pancreatic cancer cells.","authors":"Agnieszka Kurdyn, Monika Pawłowska, Ewa Paluszkiewicz, Mirosława Cichorek, Ewa Augustin","doi":"10.1007/s43440-024-00658-6","DOIUrl":"10.1007/s43440-024-00658-6","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer.</p><p><strong>Methods: </strong>The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting.</p><p><strong>Results: </strong>Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs.</p><p><strong>Conclusions: </strong>UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"182-209"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of CHI3L1 decreases N-cadherin and VCAM-1 levels in glioblastoma.","authors":"Agnieszka Rusak, Marlena Gąsior-Głogowska, Azzurra Sargenti, Edward Krzyżak, Krzysztof Kotowski, Monika Mrozowska, Tomasz Górnicki, Krzysztof Kujawa, Piotr Dzięgiel","doi":"10.1007/s43440-024-00677-3","DOIUrl":"10.1007/s43440-024-00677-3","url":null,"abstract":"<p><strong>Background: </strong>The protein CHI3L1 contributes to cancer development by several mechanisms, including stimulation of angiogenesis and invasion as well as immunomodulatory effects. These properties make it a potential target for the development of targeted therapies in precision medicine. In this context, the particular potential of CHI3L1 inhibition could be considered in glioblastoma multiforme (GBM), whose tumors exhibit high levels of angiogenesis and increased CHI3L1 expression. This study aims to investigate whether inhibition of CHI3L1 in spheroids used as a GBM model affects the mechanisms of invasiveness; METHODS: We analyzed the interactions between CHI3L1 and the inhibitor G721-0282 in molecular docking and molecular dynamics (in silico) and infrared spectroscopy. Uptake of G721-0282 in GBM spheroids was measured using a label-free physical cytometer. Changes in E-, N- and VE-cadherins, VCAM-1, and EGFR were analyzed by immunohistochemical reactions, Western blot, and ddPCR methods in U-87 MG cells and GBM spheroids consisting of U-87 MG glioblastoma cells, HMEC-1 endothelial cells and macrophages; RESULTS: A direct interaction between CHI3L1 and G721-0282 was confirmed. G721-0282 decreased N-cadherins and VCAM-1 in GBM spheroids, but the changes in the 2D model of U-87 MG glioblastoma cells were different; CONCLUSION: Inhibition of CHI3L1 has the potential to reduce the invasiveness of GBM tumors. The 3D model of GBM spheroids is of great significance for investigating changes in membrane proteins and the tumor microenvironment.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"210-228"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ONC206, an imipridone derivative, demonstrates anti-colorectal cancer activity against stem/progenitor cells in 3D cell cultures and in patient-derived organoids.","authors":"Alissar Monzer, Fatima Ghamlouche, Kevork Wakimian, Farah Ballout, Samar Al Bitar, Amani Yehya, Mariam Kanso, Nour Saheb, Ayman Tawil, Samer Doughan, Maher Hussein, Deborah Mukherji, Walid Faraj, Joshua E Allen, Varun V Prabhu, Tamara Abou-Antoun, Hala Gali-Muhtasib, Wassim Abou-Kheir","doi":"10.1007/s43440-024-00676-4","DOIUrl":"10.1007/s43440-024-00676-4","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) remains one of the most frequently diagnosed and life-threatening malignancies worldwide. CRC's high recurrence rates and drug resistance have been correlated with a subpopulation of dormant slowly dividing cells termed CRC stem cells (CCSCs). Consequently, there is a pressing need to identify novel therapeutics that can effectively and specifically target CCSCs. Imipridones are promising structurally related anticancer molecules that showed efficacy in several solid and hematological preclinical models and phase I/II/III clinical trials. This study mainly aimed to assess the potential anticancer effects of ONC206, an imipridone derivative, on CRC three-dimensional in vitro culture systems using HCT116 and HT29 cells. Importantly, the study aimed at using CRC patient-derived organoids (PDOs) to test the potential therapeutic effect of ONC206.</p><p><strong>Methods: </strong>Two-dimensional cell proliferation, viability, migration, and invasion assays were used to assess the effects of ONC206 on two colorectal cancer cell lines, HCT116 and HT29, in vitro. Immunofluorescence imaging, flow cytometry, and western blot analysis were also performed to investigate the mechanism of action of this drug. Sphere formation assay and CRC PDOs were employed to evaluate the effect of ONC206 on CRC cells in a 3D setting and specifically its potency in targeting the CRC stem/progenitor subpopulation of cells.</p><p><strong>Results: </strong>Our results showed that ONC206 was more potent than its parental molecule ONC201 in inhibiting the proliferation and viability of HCT116 and HT29 cells. Moreover, ONC206 significantly reduced the migration and invasion indices of CRC cells. These effects were accompanied by an increase in reactive oxygen species (ROS) production, sub-G1 phase accumulation, and apoptosis in HCT116 and HT29 cells. Furthermore, ONC206 significantly inhibited the 3D colonospheres growth and self-renewal ability of CCSCs more potently than ONC201, which was associated with a decrease in the expression of CSC-related markers. Lastly, ONC206 significantly reduced the growth of organoids derived from CRC patients.</p><p><strong>Conclusion: </strong>Collectively, our findings demonstrate that ONC206 is an effective anticancer molecule capable of targeting CCSCs, which may represent a novel therapeutic strategy that can overcome CRC resistance and recurrence.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"229-246"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The future of metronomic chemotherapy: experimental and computational approaches of drug repurposing.","authors":"Yousef A Abdelrady, Hayam S Thabet, Ahmed M Sayed","doi":"10.1007/s43440-024-00662-w","DOIUrl":"10.1007/s43440-024-00662-w","url":null,"abstract":"<p><p>Metronomic chemotherapy (MC), long-term continuous administration of anticancer drugs, is gaining attention as an alternative to the traditional maximum tolerated dose (MTD) chemotherapy. By combining MC with other treatments, the therapeutic efficacy is enhanced while minimizing toxicity. MC employs multiple mechanisms, making it a versatile approach against various cancers. However, drug resistance limits the long-term effectiveness of MC, necessitating ongoing development of anticancer drugs. Traditional drug discovery is lengthy and costly due to processes like target protein identification, virtual screening, lead optimization, and safety and efficacy evaluations. Drug repurposing (DR), which screens FDA-approved drugs for new uses, is emerging as a cost-effective alternative. Both experimental and computational methods, such as protein binding assays, in vitro cytotoxicity tests, structure-based screening, and several types of association analyses (Similarity-Based, Network-Based, and Target Gene), along with retrospective clinical analyses, are employed for virtual screening. This review covers the mechanisms of MC, its application in various cancers, DR strategies, examples of repurposed drugs, and the associated challenges and future directions.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1-20"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive update on the potential of curcumin to enhance chemosensitivity in colorectal cancer.","authors":"Mahdi Shadnoush, Mehrnaz Momenan, Veronique Seidel, Sascha Tierling, Nayeralsadat Fatemi, Ehsan Nazemalhosseini-Mojarad, Mohammad Tayefeh Norooz, Makan Cheraghpour","doi":"10.1007/s43440-024-00652-y","DOIUrl":"10.1007/s43440-024-00652-y","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related mortality worldwide. The efficacy of chemotherapy agents in CRC treatment is often limited due to toxic side effects, heterogeneity of cancer cells, and the possibility of chemoresistance which promotes cancer cell survival through several mechanisms. Combining chemotherapy agents with natural compounds like curcumin, a polyphenol compound from the Curcuma longa plant, has been reported to overcome chemoresistance and increase the sensitivity of cancer cells to chemotherapeutics. Curcumin, alone or in combination with chemotherapy agents, has been demonstrated to prevent chemoresistance by modulating various signaling pathways, reducing the expression of drug resistance-related genes. The purpose of this article is to provide a comprehensive update on studies that have investigated the ability of curcumin to enhance the efficacy of chemotherapy agents used in CRC. It is hoped that it can serve as a template for future research on the efficacy of curcumin, or other natural compounds, combined with chemotherapy agents to maximize the effectiveness of therapy and reduce the side effects that occur in CRC or other cancers.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"103-123"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of puerarin on gait disturbance in a 6-hydroxydopamine mouse model of Parkinson's disease.","authors":"Na-Hyun Kim, Yukiori Goto, Young-A Lee","doi":"10.1007/s43440-024-00673-7","DOIUrl":"10.1007/s43440-024-00673-7","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a neurodegenerative disorder caused by dopamine (DA) neuronal dysfunction. Although DA agonists and N-methyl-D-aspartate receptor (NMDAR) antagonists are used to treat PD, chronic use causes severe side effects. Puerarin (PUE) is a natural bioactive compound that affects the DA system; however, its effect on PD-associated motor functions is unknown. Therefore, we investigated whether PUE treatment in a 6-hydroxydopamine (6-OHDA) PD mouse model affects motor dysfunction.</p><p><strong>Methods: </strong>Adult male ICR mice received unilateral 6-OHDA microinfusion into the right medial forebrain bundle. After a 2-week recovery period, PUE (20 or 50 mg/kg) or the vehicle (saline, VEH) was administered intraperitoneally once daily for 21 days. Motor dysfunction was assessed using the locomotion, gait cycle, and rotation tests. Local field potentials (LFPs) were measured in the substantia nigra compacta (SNc), striatum (STR), subthalamic nucleus (STN), and primary motor cortex.</p><p><strong>Results: </strong>6-OHDA-lesioned PD mice showed increased gait cycle disturbance and unidirectional rotation. PUE treatment ameliorated the gait cycle disturbance, but not unidirectional rotation of PD mice. These effects differed with DA agonist treatment (which improved PD symptoms) and NMDAR antagonist treatment (which aggravated PD symptoms). Moreover, locomotion was increased only in NMDAR antagonist treatment. PUE treatment induced no changes in the attenuated LFP of the beta wave in the STR and STN, and SNc-STN delta-wave coherence was shown in PD animals.</p><p><strong>Conclusions: </strong>This study suggests that PUE is a beneficial co-therapeutic agent for alleviating gait cycle disturbance in PD symptoms.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"247-259"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}