European journal of pharmacology最新文献

{"title":"The therapeutic potential of glycyrrhizic acid and its metabolites in neurodegenerative diseases: Evidence from animal models","authors":"Xiansi Zeng ,&nbsp;Zixuan Sheng ,&nbsp;Yuqian Zhang ,&nbsp;Jing Xiao ,&nbsp;Yang Li ,&nbsp;Jiaping Zhang ,&nbsp;Guangtao Xu ,&nbsp;Jinjing Jia ,&nbsp;Min Wang ,&nbsp;Li Li","doi":"10.1016/j.ejphar.2024.177098","DOIUrl":"10.1016/j.ejphar.2024.177098","url":null,"abstract":"<div><div>Neurodegenerative diseases, mostly occurring in the elderly population, are the significant cause of disability and death worldwide. The pathogenesis of neurodegenerative diseases is still largely unknown yet, although they have been continuously explored. Thus, there is still a lack of safe, effective, and low side effect drugs in clinical practice for the treatment of neurodegenerative diseases. Pieces of accumulating evidence have demonstrated that licorice played neuroprotective roles in various neurodegenerative diseases. In the past two decades, increasing studies have indicated that glycyrrhizic acid (GL), the main active ingredient from traditional Chinese medicine licorice (widely used in the food industry) and a triterpenoid saponin with multiple pharmacological effects (such as anti-oxidant, anti-inflammatory, and immune regulation), and its metabolites (glycyrrhetinic acid and carbenoxolone) play a neuroprotective role in a range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and epilepsy. This review will elaborate on the multiple neuroprotective mechanisms of GL and its metabolites in this series of diseases, aiming to provide a basis for further research on these protective drugs for neurodegenerative diseases and their clinical application. In summary, GL may be a promising candidate drug for the therapy of neurodegenerative diseases.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177098"},"PeriodicalIF":4.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603728","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":"Transforming growth factor-β1 mediates the beneficial effects of arketamine on demyelination and remyelination in the brains of cuprizone-treated mice","authors":"Ming-ming Zhao ,&nbsp;Ting-ting Zhu ,&nbsp;Dan Xu ,&nbsp;Xiayun Wan ,&nbsp;Guilin Liu ,&nbsp;Rumi Murayama ,&nbsp;Yi Cai ,&nbsp;Yong Yue ,&nbsp;Xing-ming Wang ,&nbsp;Jian-jun Yang ,&nbsp;Kenji Hashimoto","doi":"10.1016/j.ejphar.2024.177096","DOIUrl":"10.1016/j.ejphar.2024.177096","url":null,"abstract":"<div><div>The novel antidepressant arketamine, the (<em>R</em>)-enantiomer of ketamine, has been shown to ameliorate demyelination and facilitate remyelination in the brains of cuprizone (CPZ)-treated mice. However, the mechanisms behind its effects remain unclear. Given the role of transforming growth factor β1 (TGF-β1) in arketamine's antidepressant-like effects, we examined whether TGF-β1 also plays a role in arketamine's effects on demyelination and remyelination in CPZ-treated mice. Additionally, we investigated the effects of intranasal TGF-β1 on demyelination and remyelination in these mice. Repeated intermittent administration of arketamine (10 mg/kg/day, twice weekly for the last 2-weeks) attenuated demyelination in the corpus callosum (CC) of CPZ (6 weeks)-treated mice. Furthermore, pretreatment with RepSox (10 mg/kg/day), an inhibitor of the TGF-β receptor 1, significantly blocked the beneficial effects of arketamine on the demyelination in the CC of CPZ-treated mice. Additionally, repeated intermittent administration of TGF-β1 (3.0 μg/kg/day, twice weekly for 2 weeks) significantly ameliorated demyelination and facilitated remyelination in the CC of CPZ-treated mice. These data suggest that arketamine can mitigate demyelination and facilitates remyelination in the brains of CPZ-treated mice through a TGF-β1-dependent mechanism.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177096"},"PeriodicalIF":4.2,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582419","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":"Are we better together? Addressing a combined treatment of pitavastatin and temozolomide for brain cancer","authors":"João Basso ,&nbsp;Ana Miguel Matos ,&nbsp;Saeid Ghavami ,&nbsp;Ana Fortuna ,&nbsp;Rui Vitorino ,&nbsp;Carla Vitorino","doi":"10.1016/j.ejphar.2024.177087","DOIUrl":"10.1016/j.ejphar.2024.177087","url":null,"abstract":"<div><div>Pitavastatin is commonly prescribed to treat hypercholesterolemia through the regulation of cholesterol biosynthesis. Interestingly, it has also demonstrated a great potential for treating brain tumors, although the detailed cytotoxic mechanism, particularly in glioblastoma, remains incompletely understood. This work explores the activity of pitavastatin in 2D and 3D glioblastoma models, in an attempt to provide a more representative and robust overview of its anticancer potential in glioblastoma. The results show that not only is pitavastatin 10-1000 times-fold more effective in reducing tumoral metabolic activity than temozolomide, but also demonstrate a synergistic activity with this alkylating drug. In addition, low micromolar concentrations of this statin strongly impair the growth and the invasion ability of multicellular tumor spheroids. The obtained qRT-PCR and proteomics data highlight the modulation of cell death via apoptosis (<em>BAX/BCL2, CASP9</em>) and autophagy (<em>BECN1, BNIP3</em>, <em>BNIP3L</em> and <em>LC3B</em>), as well as an epithelial to mesenchymal transition blockage (HTRA1, SERPINE1, WNT5A, ALDH3B1 and EPHA2) and remodeling of the extracellular matrix (VCAN, SERPINE1 and TGFBI). Overall, these results lay the foundation for further investigations on the potential combinatory clinical treatment with temozolomide.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177087"},"PeriodicalIF":4.2,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567964","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":"The next frontier in multiple sclerosis therapies: Current advances and evolving targets","authors":"K. Trideva Sastri ,&nbsp;N. Vishal Gupta ,&nbsp;Anbarasu Kannan ,&nbsp;Suman Dutta ,&nbsp;Riyaz Ali M Osmani ,&nbsp;Balamuralidhara V ,&nbsp;A. Ramkishan ,&nbsp;Shanmuganathan S","doi":"10.1016/j.ejphar.2024.177080","DOIUrl":"10.1016/j.ejphar.2024.177080","url":null,"abstract":"<div><div>Recent advancements in research have significantly enhanced our comprehension of the intricate immune components that contribute to multiple sclerosis (MS) pathogenesis. By conducting an in-depth analysis of complex molecular interactions involved in the immunological cascade of the disease, researchers have successfully identified novel therapeutic targets, leading to the development of innovative therapies. Leveraging pioneering technologies in proteomics, genomics, and the assessment of environmental factors has expedited our understanding of the vulnerability and impact of these factors on the progression of MS. Furthermore, these advances have facilitated the detection of significant biomarkers for evaluating disease activity. By integrating these findings, researchers can design novel molecules to identify new targets, paving the way for improved treatments and enhanced patient care. Our review presents recent discoveries regarding the pathogenesis of MS, highlights their genetic implications, and proposes an insightful approach for engaging with newer therapeutic targets in effectively managing this debilitating condition.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177080"},"PeriodicalIF":4.2,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568049","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":"Demyelination in cuprizone mice is ameliorated by calycosin mediated through astrocyte Nrf2 signaling pathway","authors":"Yuxin Chen ,&nbsp;Yuanhua Wang ,&nbsp;Qijin Lu ,&nbsp;Yan Zhao ,&nbsp;Jennifer Cruz ,&nbsp;Jinyun Ma ,&nbsp;Guiqing Ding ,&nbsp;Xi Qiao ,&nbsp;Xiaodong Cheng","doi":"10.1016/j.ejphar.2024.177090","DOIUrl":"10.1016/j.ejphar.2024.177090","url":null,"abstract":"<div><div>Oxidative stress plays a pivotal role in multiple sclerosis (MS), triggering demyelination predominantly through excessive peroxide production and the depletion of antioxidants. The accumulation of oxidative damage can be caused by dysregulation of astrocytes, which are the brain's main regulators of oxidative homeostasis. Calycosin, an essential bioactive component extracted from Astragalus, is recognized for its neuroprotective properties. Although recent research has highlighted calycosin's neuroprotective capabilities, its role in demyelinating conditions like MS remains unclear. In this work, we examined the possible molecular mechanism of calycosin's neuroprotective effect on cuprizone (CPZ)-induced demylination in mice. According to our research, calycosin successfully reduced demyelination and behavioral dysfuction in CPZ mice. Calycosin also decreased the production of oxidative stress and enhanced the expression of antioxidants in CPZ mice and in astrocytes induced by hydrogen peroxide (H₂O₂). Furthermore, both <em>in vivo</em> and <em>in vitro</em> experiments demonstrated that calycosin promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) along with the upregulation of heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and superoxide dismutase (SOD). Importantly, the application of all-trans retinoic acid (ATRA), a specific inhibitor of Nrf2, effectively reversed the myelin-protective and antioxidant effects conferred by calycosin. This study suggested that calycosin might exert neuroprotection by inhibiting oxidative stress and reducing demyelination via the activation of astrocyte Nrf2 signaling. These findings indicated that calycosin might be a potential candidate for treating MS.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177090"},"PeriodicalIF":4.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568021","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":"Novel apocynin regulates TRPV1 activity in the trigeminal system and controls pain in a temporomandibular joint neurogenic model","authors":"Taisa Maria Mendes Matuiama Machado ,&nbsp;Iara Gonçalves Aquino ,&nbsp;Marcelo Franchin ,&nbsp;Miguel O. Zarraga ,&nbsp;Daniel Bustos ,&nbsp;Fernanda Papa Spada ,&nbsp;Marcelo Henrique Napimoga ,&nbsp;Juliana Trindade Clemente-Napimoga ,&nbsp;Severino Matias Alencar ,&nbsp;Bruna Benso ,&nbsp;Henrique Ballassini Abdalla","doi":"10.1016/j.ejphar.2024.177093","DOIUrl":"10.1016/j.ejphar.2024.177093","url":null,"abstract":"<div><h3>Objective</h3><div>Herein, we investigate the potential analgesic effect of a newly synthesized chalcone-derived apocynin in a neurogenic pain model.</div></div><div><h3>Methods</h3><div>Molecular docking was used to foretell the apocynin binding features and dynamics with the TRPV1 channel, and the activity was tested <em>in vitro</em>, using transfected HEK 293T cells with the rat TRPV1 receptor. The analgesic effect of apocynin was investigated using a capsaicin-induced pain model. The expression of TRPV1, TRPA1, TRPM8, and MAPKs was assessed by electrophoresis, and immunosorbent assays were performed to quantify the neurotransmitters Substance P, Glutamate, and CGRP. A survival assay using <em>Galleria mellonella</em> was carried out to determine the toxicity.</div></div><div><h3>Results</h3><div>We observed that apocynin exhibits greater thermodynamic stability. Upon apocynin ligand binding, it changes the electrostatic potential for a predominantly electronegative state in the interior and neutral in its external vanilloid pocket. Treatment of apocynin induces antinociceptive effects against the noxious challenge of capsaicin. Histologically, apocynin decreased the number of TRPV1⁺ immunopositive cells. Electrophoresis showed reduced phosphorylation of p44/42 (ERK1/2) and decreased protein levels of substance P, and CGRP. In the survival assay, apocynin showed low toxicity.</div></div><div><h3>Conclusions</h3><div>In conclusion, we provide proof-of-principles that the newly synthesized apocynin compound effectively prevented nociception in a neurogenic model of orofacial pain.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177093"},"PeriodicalIF":4.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568043","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":"Cordycepin enhances the Anticancer efficacy of PD-L1 blockade by modulating the tumor microenvironment of colon cancer","authors":"Chen Feng ,&nbsp;Rongzhang Chen ,&nbsp;Xinran Gao ,&nbsp;Weiwei Fang ,&nbsp;Shaoxian Wu ,&nbsp;Lujun Chen ,&nbsp;Xiao Zheng ,&nbsp;Xinyue Ji ,&nbsp;Maoling Yuan ,&nbsp;Yuanyuan Fu ,&nbsp;Hanjie Ying ,&nbsp;Tao Shen ,&nbsp;Dawei Zhu ,&nbsp;Jingting Jiang","doi":"10.1016/j.ejphar.2024.177089","DOIUrl":"10.1016/j.ejphar.2024.177089","url":null,"abstract":"<div><h3>Background</h3><div>PD-L1 blockade has been found to be effective in treating multiple malignancies. Combined therapy is proposed to provide better therapeutic effects. Cordycepin, a prominent bioactive compound found in cordyceps, can inhibit the development of various cancers.</div></div><div><h3>Purpose</h3><div>This study aimed to determine the efficacy of combined anti-PD-L1 antibody and cordycepin in tumor treatment.</div></div><div><h3>Methods</h3><div>A single-cell RNA sequencing was used to analyze the mechanism of combined treatment.</div></div><div><h3>Results</h3><div>Combination therapy of anti-PD-L1 and cordycepin significantly inhibited tumor growth by regulating the T cell ratio and improving the function of CD8⁺T cells. Furthermore, cordycepin promoted the reprogramming of type-II macrophages into type-I macrophages, a process confirmed through flow cytometry analysis of the underlying mechanism.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that the combination of anti-PD-L1 and cordycepin effectively suppressed tumor growth by regulating the proportion of T cells and reprograming type-II macrophages.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177089"},"PeriodicalIF":4.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567990","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":"GPR55 antagonist CID16020046 suppresses DNCB-induced atopic dermatitis-like symptoms by suppressing Th1/Th2/Th17 populations in mice","authors":"So-Eun Son ,&nbsp;Dong-Soon Im","doi":"10.1016/j.ejphar.2024.177088","DOIUrl":"10.1016/j.ejphar.2024.177088","url":null,"abstract":"<div><div>G protein-coupled receptor 55 (GPR55) is a lipid-sensing receptor that plays a role as an immune mediator and is primarily upregulated during immune cell activation. There is a lack of knowledge about the role of GPR55 in allergic inflammatory diseases such as atopic dermatitis. The purpose of this study was to investigate the role of GPR55 through the use of its antagonist, CID16020046, in an atopic dermatitis mouse model. It was found that BALB/c mice develop lesions similar to those associated with atopic dermatitis following sensitization and repeated exposure to 1-chloro-2,4-dinitrobenzene (DNCB). It was found that CID16020046 (1 mg/kg, i. p.) alleviated the atopic dermatitis-like symptoms as well as immune dysregulation caused by DNCB. Based on histopathological analysis, CID16020046 reduced ear thickening and mast cell counts in the dermis. CID16020046 decreased DNCB-induced increases in serum IgE levels, as measured using enzyme-linked immunosorbent assays. A significant reduction in lymph node hypertrophy was also observed with CID16020046 as well as significant reductions in CD4⁺ T helper 1 (Th1), Th2, and Th17 cells in the lymph nodes. As a result of the administration of CID16020046, cytokines of Th1 (IFN-γ), Th2 (IL-4 and IL-13), and Th17 (IL-17 A) types were also reduced in the skin and lymph nodes. In conclusion, blocking GPR55 alleviates DNCB-induced atopic dermatitis-like symptoms, suggesting that GPR55 is a potential therapeutic target for allergic inflammatory diseases via immunoregulation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177088"},"PeriodicalIF":4.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564146","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":"miR-421-mediated suppression of FGF13 as a novel mechanism ameliorates cardiac hypertrophy by inhibiting endoplasmic reticulum stress","authors":"Yaxin Zhi ,&nbsp;Yanru Duan ,&nbsp;Ying Zhang ,&nbsp;Haijuan Hu ,&nbsp;Fengli Hu ,&nbsp;Pengfei Wang ,&nbsp;Bin Liu ,&nbsp;Chuan Wang ,&nbsp;Demin Liu ,&nbsp;Guoqiang Gu","doi":"10.1016/j.ejphar.2024.177085","DOIUrl":"10.1016/j.ejphar.2024.177085","url":null,"abstract":"<div><div>Pathological cardiac hypertrophy is an independent risk factor for heart failure. Currently, clinical treatments offer limited effectiveness, and both mortality and morbidity from cardiac hypertrophy and heart failure continue to be significant. Therefore, it is extremely urgent to find new intervention targets to prevent and alleviate pathological cardiac hypertrophy. In this study, we explored FGF13 expression and its upstream regulators in hypertrophic hearts. Firstly, we observed an increase in FGF13 expression levels in human hypertrophic myocardium tissues, as well as in mouse models of TAC-induced hypertrophy and in neonatal rat cardiomyocyte (NRCM) models induced by isoproterenol (ISO). Moreover, these elevated levels of FGF13 were shown to positively correlate with hypertrophic markers, including ANP and BNP. By using both gain-of-function and loss-of-function approaches in an in vitro hypertrophy model, we demonstrated that FGF13 knockdown could inhibit endoplasmic reticulum stress (ERS), thereby ameliorating cardiomyocyte hypertrophy. Meanwhile, we investigated the upstream regulators of FGF13 in hypertrophic hearts, and a dual-luciferase reporter assay confirmed that FGF13 is a direct target of miR-421. Overexpression of miR-421 decreased the protein level of FGF13 and ameliorated ISO-induced cardiomyocyte hypertrophy via modulating ER stress. In contrast, overexpression of FGF13 attenuated the ameliorative effect of miR-421 on ISO-induced cardiomyocyte hypertrophy. Taken together, the present results suggested that miR-421 ameliorated ISO-induced cardiomyocyte hypertrophy by negatively regulating FGF13 expression. This finding may offer a novel approach for the treatment of cardiac hypertrophy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177085"},"PeriodicalIF":4.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564091","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":"H2S protects rat cerebral ischemia-reperfusion injury by inhibiting expression and activation of hippocampal ROCK2 at the Thr436 and Ser575 sites","authors":"Fang Fang ,&nbsp;Yi-Ning Guan ,&nbsp;Mei-Jing Zhong ,&nbsp;Ji-Yue Wen ,&nbsp;Zhi-Wu Chen","doi":"10.1016/j.ejphar.2024.177079","DOIUrl":"10.1016/j.ejphar.2024.177079","url":null,"abstract":"<div><h3>Background</h3><div>H₂S is an endogenous gas signal molecule, which protects cerebral ischemia/reperfusion (I/R) injury by phosphorylating rho-associated coiled coil-containing protein kinase 2 (ROCK₂) at Tyr722, and inhibiting ROCK₂ protein expression and activities. We previously reported that H₂S protected rat neurons from hypoxia/reoxygenation injury in vitro through inhibiting phosphorylation of ROCK₂ at Thr436 and Ser575, but it is unclear whether these two sites are involved in protection of H₂S against cerebral I/R injury.</div></div><div><h3>Method</h3><div>Rats transfected with wild-type and mutant eukaryotic plasmids of ROCK₂ in hippocampus were used to establish I/R model by ligating bilateral common carotid artery. Rat behavioral deficit was detected by water maze assay, and ROCK₂, lactate dehydrogenase (LDH), nerve-specific enolase (NSE) and reactive oxygen species (ROS) were determined by ELISA. ROCK₂ expressions was examined by western-blot assay, and bcl-2 and Bax mRNAs were examined by RT-qPCR.</div></div><div><h3>Results</h3><div>NaHS (4.8 mg/kg) significantly inhibited the I/R-increased serum LDH, NSE and ROS in the ROCK₂^wild-pEGFP-N1-transfected rats, but had no obvious effect in the ROCK₂^T436A-pEGFP-N1- or the ROCK₂^S575F-pEGFP-N1-transfected rats; inhibitions of NaHS on the I/R-increased escape latency and the I/R-decreased percentage of target quadrant distance to total distance were markedly attenuated or abolished in the ROCK₂^T436A-pEGFP-N1- or the ROCK₂^S575F-pEGFP-N1-transfected rats compared with those in the ROCK₂^wild-pEGFP-N1-transfected rats; NaHS obviously inhibited the I/R-increased hippocampal ROCK₂ and GFP-ROCK₂ proteins, Bax mRNA, and ROCK₂ activity, as well as the I/R-decreased hippocampal bcl-2 mRNA in the hippocampus of the ROCK₂^wild-pEGFP-N1-transfected rats, but had no significant effect in the ROCK₂^T436A-pEGFP-N1- or the ROCK₂^S575F-pEGFP-N1-transfected rats.</div></div><div><h3>Conclusion</h3><div>H₂S protects cerebral I/R injury in rats by inhibiting expression and activation of hippocampal ROCK₂ via the Thr436 and Ser575 sites.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177079"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564090","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}