Biomedicine & Pharmacotherapy最新文献

{"title":"Lower hepatotoxicity risk in Xelaglifam, a novel GPR40 agonist, compared to Fasiglifam for type 2 diabetes therapy","authors":"Jongmin Yoon ,&nbsp;Haengjin Song ,&nbsp;Ji Soo Park ,&nbsp;Jeong Ho Kim ,&nbsp;Yearin Jun ,&nbsp;Sang-Ah Gim ,&nbsp;Changhee Hong ,&nbsp;Kyung Mi An ,&nbsp;Joon-Tae Park ,&nbsp;Jung Woo Lee ,&nbsp;Hongchul Yoon ,&nbsp;Yun Seok Kim ,&nbsp;Sang Geon Kim","doi":"10.1016/j.biopha.2024.117674","DOIUrl":"10.1016/j.biopha.2024.117674","url":null,"abstract":"<div><div>Fasiglifam, a candidate targeting GPR40, showed efficacy in clinical trials for type 2 diabetes but exerted liver toxicity. This study investigated the drug-induced liver injury (DILI) risk of Xelaglifam, a new GPR40 agonist, based on the potential toxicity mechanism of Fasiglifam; transporter inhibition, mitochondrial dysfunction, reactive metabolite formation, and covalent binding to proteins. In the hepatobiliary transporter assay, Xelaglifam showed a broader safety margin (&gt;10-fold) against bile acid transporters, suggesting its less likelihood to cause bile acids accumulation, unlike Fasiglifam (&lt;10-fold safety margin). Moreover, Xelaglifam showed no effect on glycocholic acid accumulation at higher concentrations than the estimated C_max in the 3D human liver model, whereas Fasiglifam affected the accumulation. In the HepaRG spheroids 3D model, the AC₅₀ values of Xelaglifam for mitochondrial function-related parameters were higher than Fasiglifam. Unlike Fasiglifam, none of the cell parameters for Xelaglifam were below the estimated 5x C_max. Additionally, the glucuronide metabolite of Xelaglifam was negligible (&lt;1 % of the parent) in the Safety Testing, indicating a limited contribution to DILI. Fasiglifam activated genes related to liver disease, whereas Xelaglifam had no effect; instead, it increased FXR activity, a bile acid regulator. Notably, toxicity studies in rats and monkeys showed no adverse liver effects at higher exposure levels than the effective human blood concentration. Overall, these results support a low risk of DILI for Xelaglifam treatment and the justification for its long-term use for treating type 2 diabetes.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117674"},"PeriodicalIF":6.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634504","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":"Diabetes and the associated complications: The role of antioxidants in diabetes therapy and care","authors":"Lowell Dilworth ,&nbsp;Dewayne Stennett ,&nbsp;Aldeam Facey ,&nbsp;Felix Omoruyi ,&nbsp;Shada Mohansingh ,&nbsp;Felix O. Omoruyi","doi":"10.1016/j.biopha.2024.117641","DOIUrl":"10.1016/j.biopha.2024.117641","url":null,"abstract":"<div><div>Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high blood sugar levels (hyperglycemia). Poorly managed diabetes can lead to complications affecting multiple organ systems. Antioxidants play a crucial role in reducing oxidative stress caused by reactive oxygen species (ROS), primarily triggered by uncontrolled high blood sugar levels in diabetes. Antioxidants like vitamin C, E, selenium, and alpha-lipoic acid, when used as supplements, have shown promise in reducing oxidative stress markers and improving antioxidant status in laboratory and animal studies and diabetic patients. Antioxidant supplementation may help reduce the risk of diabetic complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Additionally, antioxidants also have anti-inflammatory properties, which could be beneficial in reducing inflammation associated with diabetes. Antioxidant supplementation has been shown to enhance endothelial function, insulin sensitivity, and glucose metabolism, thereby aiding in glycemic control and overall diabetic management. Combining antioxidants with certain medications may have therapeutic benefits, such as effectively neutralizing free radicals and enhancing the regulation of antioxidant defense systems. This review presents an update on diabetes, the sources of free radical generation, the body's natural defense mechanisms, the clinical evidence regarding using antioxidants in managing diabetic complications, and the potential new therapeutic approaches. Overall, antioxidant supplementation may offer some benefits in managing diabetic complications. However, further studies are needed to understand the mechanisms of action, determine the optimal supplementation, explore potential interactions with other medications, and conduct long-term studies to establish the possible use of antioxidants for optimal benefits in diabetes care.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117641"},"PeriodicalIF":6.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634482","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":"Preparation and evaluation of Puerarin-loaded PLGA nanoparticles for improving oral bioavailability in SD rats","authors":"Lili Zhang ,&nbsp;Chengcheng Duan ,&nbsp;Shiquan Feng ,&nbsp;Beicheng Zhao ,&nbsp;Hailong Li ,&nbsp;Xi Zhang ,&nbsp;Yan Zhou ,&nbsp;Zhenmiao Qin","doi":"10.1016/j.biopha.2024.117670","DOIUrl":"10.1016/j.biopha.2024.117670","url":null,"abstract":"<div><h3>Background</h3><div>Puerarin (Pue) is an isoflavone compound with significant therapeutic effect on cardiovascular diseases, but its poor water solubility and low oral bioavailability limit clinical application.</div></div><div><h3>Methods</h3><div>In this study, Pue was prepared into PLGA nanoparticles (Pue-PLGA NPs) by emulsion solvent volatilization method. The morphology, particle size, Zeta potential, X-ray diffraction (XRD), and fourier transform infrared (FTIR) of the NPs were characterized. Additionally, their stability and in vitro release were evaluated. SD rats were orally administered wtih Pue and Pue-PLGA NPs, and a high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established to determine the concentration of blood samples and to investigate the pharmacokinetic behaviour of Pue and Pue-PLGA NPs in rats.</div></div><div><h3>Results</h3><div>The NPs were observed by transmission electron microscopy (TEM) as regular spheroids and uniformly dispersed. The average particle size of the NPs was (167.1±5.26）nm, the Zeta potential was (-29.88±2.46)mV, the encapsulation rate was (83.12 %±4.73 %) and the drug loading capacity was (7.75 %±1.81 %). The results of in vitro release showed that the drug was released slowly and continuously from the NPs, reaching the release platform in 24 h, and the cumulative release amount was (88.55±2.86) %. The pharmacokinetic results showed that the AUC_0–24, AUC_0-∞, C_max, T_max, t_1/2, MRT_0–24 and MRT_0-∞ of Pue-PLGA NPs were 2.196, 1.978, 1.327, 1.5, 1.385, 3.915 and 3.140 times of Pue, respectively. The relative bioavailability was (197.82±25.28) %.</div></div><div><h3>Conclusion</h3><div>These results indicated that the prepared nanoparticles had small particle size, high encapsulation rate, drug loading capacity and good slow-release effect, and could significantly improve the oral bioavailability of Pue in rats.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117670"},"PeriodicalIF":6.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633009","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":"Semaglutide decelerates the growth and progression of breast cancer by enhancing the acquired antitumor immunity","authors":"Isidora Stanisavljevic ,&nbsp;Sladjana Pavlovic ,&nbsp;Bojana Simovic Markovic ,&nbsp;Milena Jurisevic ,&nbsp;Tamara Krajnovic ,&nbsp;Sanja Mijatovic ,&nbsp;Marija Spasojevic ,&nbsp;Slobodanka Mitrovic ,&nbsp;Irfan Corovic ,&nbsp;Ivan Jovanovic","doi":"10.1016/j.biopha.2024.117668","DOIUrl":"10.1016/j.biopha.2024.117668","url":null,"abstract":"<div><div>Semaglutide, a glucagon-like peptide 1 receptor agonist, is an antidiabetic that has recently shown promising immunomodulatory and antitumor effects. Breast cancer is the most common type of cancer affecting women worldwide. The aim of this study was to analyze the effects of semaglutide on the antitumor immunity in a 4T1 mouse breast cancer model. After induction of breast cancer, BALB/C mice were treated intraperitoneally with semaglutide. Semaglutide administration decelerated tumor appearance, growth and progression. The antidiabetic drug showed neither a direct cytotoxic effect <em>in vitro</em>, nor an angiogenic effect. Furthermore, depletion of NK cells had no affect on tumor growth in semaglutide treated mice suggesting a non-NK cell-dependent mechanism. However, semaglutide increased the accumulation and maturation of CD11c⁺ dendritic cell, while decreasing the percentage of FoxP3⁺ regulatory T cells in the spleen and primary tumor. In addition, semaglutide increased tumor infiltration and promoted the antitumor phenotype of T cells, <em>in vivo</em>. Furthermore, semaglutide enhanced the cytotoxic capacity of CD8⁺ T cells, <em>in vitro.</em> These results suggest that semaglutide enhances the acquired antitumor immune response and has potential for the future treatment of malignancies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117668"},"PeriodicalIF":6.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633413","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":"Neuroprotective effects of Elaeagnus glabra f. oxyphylla extract in amyloid-beta-induced cognitive deficit mice: Involvement of the PKC-delta, MYL2, and FER pathways","authors":"Eunjin Sohn ,&nbsp;Hye-Sun Lim ,&nbsp;Bu-Yeo Kim ,&nbsp;Yu Jin Kim ,&nbsp;Joo-Hwan Kim ,&nbsp;Soo-Jin Jeong","doi":"10.1016/j.biopha.2024.117671","DOIUrl":"10.1016/j.biopha.2024.117671","url":null,"abstract":"<div><div><em>Elaeagnus glabra</em> f. <em>oxyphylla</em> (EGFO), a member of the <em>Elaeagnaceae</em> family, is an evergreen plant distinct from other species in its genus<em>.</em> We previously reported that ethanol extract from EGFO has memory improvement effects in a short-term memory deficit mouse model and anti-inflammatory effects in a microglial cell line. However, little is known about the pharmacological effects of EGFO. In the present study, we further explored the effect of EGFO on cognitive impairment using amyloid-beta-induced Alzheimer's disease (AD)-like mice. EGFO extract significantly enhanced cognitive functions in the passive avoidance task and Morris water maze test. EGFO treatment led to a significant increase in neuronal nuclei expression in mouse hippocampal tissues and inhibited hydrogen peroxide-induced cell death in HT22 hippocampal cells, indicating the neuroprotective effects of EGFO. Antibody microarray analysis was performed to determine the molecular mechanisms underlying the effects of EGFO on cognitive improvement and neuroprotection. The data revealed that EGFO decreased the phosphorylation of protein kinase C delta and increased the phosphorylation of myosin regulatory light chain 2 and tyrosine kinase Fer. These findings were validated using immunoblotting both in <em>in vitro</em> and <em>in vivo</em> AD models. Overall, our findings suggest that EGFO could be a candidate therapeutic agent for AD or AD-like diseases due to its potential for cognitive improvement and neuroprotection.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117671"},"PeriodicalIF":6.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632735","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":"Insights on neuropharmacological benefits and risks: Aconitum carmichaelii Debx.","authors":"Xiuyun Liu ,&nbsp;Xin Song ,&nbsp;Kuo Zhang ,&nbsp;Peng Wang ,&nbsp;Yiwen Wang ,&nbsp;Guoxin Han ,&nbsp;Yunfei Du ,&nbsp;Meijun Pang ,&nbsp;Dong Ming","doi":"10.1016/j.biopha.2024.117669","DOIUrl":"10.1016/j.biopha.2024.117669","url":null,"abstract":"<div><div><em>Aconitum carmichaelii</em> Debx., a traditional herb known for its potent bioactivities, has been widely used in Traditional Chinese Medicine, particularly in the forms of <em>Chuanwu</em> and <em>Fuzi.</em> Despite the therapeutic benefits of this plant, concerns have been raised regarding its neuropharmacological actions and potential neurotoxicity. This paper provides an in-depth analysis of the neuropharmacological effects, neurotoxicological mechanisms, and toxicity biomarkers of <em>Aconitum roots</em>. The neuropharmacological properties are linked to alterations in neurotransmitter synthesis and ion transport modulation, while the neurotoxic effects are primarily attributed to oxidative stress responses and the induction of mitochondrial apoptosis pathways. Through metabolomic profiling, we have identified several metabolic pathways affected by <em>Aconitum roots</em>, with a significant impact on tryptophan metabolism, which in turn influences cardiovascular and nervous system functions, liver detoxification, and energy metabolism. Furthermore, we discuss the modulation of ion channel protein activity, which is evidenced by recent studies, suggesting a critical role in the neurotoxic effects of <em>Aconitum</em>. An early detection strategy for toxicity biomarkers using metabonomics is proposed, emphasizing its crucial role in enhancing the diagnosis and treatment of <em>Aconitum</em> poisoning. It is recommended that regular monitoring of individuals at risk of <em>Aconitum</em> toxicity, including habitual consumers of TCM and accidental ingestion of the plant, be conducted in order to prevent toxic outcomes. This review emphasizes the importance of understanding the dual nature of <em>Aconitum</em> as both a therapeutic agent and a potential neurotoxin, aiming to optimize its clinical use and ensure patient safety.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117669"},"PeriodicalIF":6.9,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634500","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":"Evaluating the potential of off-the-shelf engineered mesenchymal stem cells for targeted Hepatocellular Carcinoma treatment: A multisite proof-of-concept study","authors":"Xiao Ni Ma ,&nbsp;Yoon Khei Ho ,&nbsp;Jian Yi Gerald Goie ,&nbsp;Cheng-Xu Ma ,&nbsp;Zong-Bin Sun ,&nbsp;Li-Qiong Yao ,&nbsp;Xiao Liang Zhu ,&nbsp;Jun Yung Woo ,&nbsp;Heng-Phon Too ,&nbsp;Xun Li","doi":"10.1016/j.biopha.2024.117676","DOIUrl":"10.1016/j.biopha.2024.117676","url":null,"abstract":"<div><div>Although combining 5-fluorouracil (5-FU) and Interferon-beta (IFNb) improves response rates in Hepatocellular Carcinoma (HCC), the outcomes remain suboptimal. This study investigates the feasibility of using highly transfected Mesenchymal Stem Cells (MSCs) to deliver a chemotherapeutic (5-FU) and an immunomodulator (IFNb) for localized HCC treatment. Considering the crucial role of cold-chain transportation in off-the-shelf allogeneic therapy, the study also assesses the quality and efficacy of frozen-thawed engineered MSCs, simulating a multisite study process. The engineered MSCs maintained their phenotypes and tumour tropism. With just 10 % engineered MSCs, a killing efficiency of over 70 % was achieved in Huh-7 and HepG2 cell lines in vitro. Coculture studies, soft agar assays, and in vivo experiments confirmed that MSCs are neither tumorigenic nor tumour-promoting. Tumour mass growth was inhibited by &gt;80 % in the treated mice group. TUNEL, Annexin-V, and Ki67 staining confirmed DNA damage, cell death, and proliferation inhibition post-treatment. Blood chemistry and the weight of the mice were comparable to the control group, indicating a good safety profile. This proof-of-concept study demonstrates the efficacy and safety of off-the-shelf CDUPRT-IFNβ_MSCs in targeting hepatocellular carcinoma (HCC) growth. Evaluating the complete value chain of MSC therapy in early-stage preclinical studies is essential for justifying further investigation and clinical translation of this cell product.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117676"},"PeriodicalIF":6.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634485","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":"Phase separation of epigenetic landscape in cardiovascular diseases","authors":"Sui Mao ,&nbsp;Zhen-Yu Liu ,&nbsp;Zhi-Yan Liu ,&nbsp;Peng Liu ,&nbsp;Li-Chan Lin ,&nbsp;Ye Zhang ,&nbsp;Jing-Jing Yang ,&nbsp;Jian-Yuan Zhao ,&nbsp;Hui Tao","doi":"10.1016/j.biopha.2024.117654","DOIUrl":"10.1016/j.biopha.2024.117654","url":null,"abstract":"<div><div>The pathogenesis of cardiovascular diseases (CVDs) is intricate, with liquid-liquid phase separation (LLPS) considered a crucial regulatory mechanism. Epigenetics is closely intertwined with cardiovascular diseases, involving mechanisms such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) that play pivotal roles in cardiovascular disease progression and regression. It is known that specific proteins and mRNAs associated with epigenetic modifications exhibit LLPS characteristics, influencing cardiovascular diseases. Consequently, targeting epigenetic modifications to modulate LLPS emerges as a promising strategy for cardiovascular diseases treatment. This review delves into the regulatory impact of liquid-liquid phase separation on cardiovascular diseases, with a specific focus on the epigenetic landscape. The current study sought to investigate the relationship between epigenetic landscape and phase separation in cardiovascular diseases development, as well as their therapeutic implications.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117654"},"PeriodicalIF":6.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632893","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":"Human serum albumin promotes interactions between HSA-IL-2 fusion protein and CD122 for enhancing immunotherapy","authors":"Kaiyue Zuo ,&nbsp;Naiyu Liu ,&nbsp;Peng Zhou ,&nbsp;Mengzhu Zheng ,&nbsp;Lingjuan Wang ,&nbsp;Tingting Tang ,&nbsp;Zhanqun Yang ,&nbsp;Long Chen ,&nbsp;Xinjie Zhu","doi":"10.1016/j.biopha.2024.117664","DOIUrl":"10.1016/j.biopha.2024.117664","url":null,"abstract":"<div><div>Interleukin 2 (IL-2) is a multifunctional cytokine that is crucial for T-lymphocytes proliferation and differentiation. However, IL-2 binds to IL-2Rα (CD25) subunit preferentially and tends to stimulate regulatory T cells (Tregs), which express high-affinity trimeric receptors (IL-2Rαβγ), resulting in immunosuppressive effects. Therefore, development of methods that enhance IL-2/CD122 interactions and activate immune responses without affecting therapeutic efficacy of IL-2 may be desirable. In this work, we constructed a recombinant IL-2 fusion protein (HSA-IL-2), comprising human serum albumin (HSA) and IL-2, there was a new interaction interface between HSA domain and CD122 in HSA-IL-2 fusion protein predicted by AlphaFold2, and followed by determining binding affinity between HSA-IL-2 and CD122 through ForteBio’s Bio-Layer Interferometry technology. Strikingly, HSA did promoted interactions between HSA-IL-2 fusion protein and CD122 compared with wild-type IL-2. <em>In vivo</em> experiments, HSA-IL-2 fusion protein had capacity to promote CD8⁺ T cells infiltration while reducing Treg cells infiltration for boosting immunotherapeutic efficacy. Furthermore, it facilitated synergistic therapeutic effect with α-PD-L1 to inhibit tumor growth. Overall, our research unveiled an enhanced binding affinity method underlying interactions between IL-2 and CD122 via fusing albumin, and propose a promising therapeutic strategy to facilitate IL-2 administration and broaden its clinical use.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117664"},"PeriodicalIF":6.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634487","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":"Atorvastatin facilitates extinction and prevents reinstatement of morphine-induced conditioned place preference in rats","authors":"Shiva Hashemizadeh ,&nbsp;Elham Alaee ,&nbsp;Niloofar Aghajani ,&nbsp;Hossein Azizi ,&nbsp;Saeed Semnanian","doi":"10.1016/j.biopha.2024.117639","DOIUrl":"10.1016/j.biopha.2024.117639","url":null,"abstract":"<div><div>Opioid addiction is known as a chronic relapsing disorder associated with long-lasting molecular and cellular neuroadaptations that lead to compulsive behavior. Current pharmacotherapies target the modulation of mu-opioid receptors (MOR); however, the relapse rate remains high. In this study, we evaluated the potential effect of atorvastatin, a blood-brain barrier-permeable statin, on preventing morphine relapse through both extinction-reinstatement and abstinence-reinstatement models using conditioned place preference (CPP). Adult male Wistar rats were used to establish morphine-induced CPP (5 mg/kg), followed by extinction training and subsequent priming injection of morphine (2 mg/kg, i.p.) to induce relapse-like behavior. Extinguished rats significantly reinstated their morphine-seeking behavior. In contrast, rats that received different doses of atorvastatin (0.1, 0.5, 1 mg/kg) 1 hour before each extinction training session did not show a preference for the morphine-paired chamber. Moreover, acute atorvastatin injection (1 mg/kg, i.p.) 1 h before the reinstatement test significantly prevented reinstated morphine-seeking behavior. We found that atorvastatin 1 mg/kg attenuated morphine-seeking behaviors, and this attenuation of reinstatement was partly mediated by the upregulation of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (Hipp). Furthermore, atorvastatin reversed <em>Oprm1</em> upregulation (mu-opioid receptor gene) induced by relapse in the nucleus accumbens and Hipp. Moreover, treatment with atorvastatin during the extinction period alters the electrophysiological properties of the mPFC neurons following morphine priming and enhances neuronal excitability. We conclude that atorvastatin was effective in decreasing reinstatement.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117639"},"PeriodicalIF":6.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634480","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}