Neuroprotective effect of Kurarinone against corticosterone-induced cytotoxicity on rat hippocampal neurons by targeting BACE1 to activate P13K-AKT signaling - A potential treatment in insomnia disorder.
{"title":"Neuroprotective effect of Kurarinone against corticosterone-induced cytotoxicity on rat hippocampal neurons by targeting BACE1 to activate P13K-AKT signaling - A potential treatment in insomnia disorder.","authors":"Guoqing Wu, Yanyan Wu","doi":"10.1002/prp2.1132","DOIUrl":null,"url":null,"abstract":"<p><p>The hippocampus has been implicated in the pathogenesis of insomnia disorder (ID) and the purpose of this study was to investigate the neuroprotective mechanism of the natural flavone Kurarinone (Kur) on hippocampal neurotoxicity as a potential treatment of ID. The effect of Kur on hippocampal neuronal cell (HNC) viability and apoptosis were assessed by Cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. Then, the effect of Kur on β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), brain-derived neurotrophic factor (BDNF), and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) phosphorylation level were measured by Western blot. Further, SwissTargetPrediction analysis and molecular docking experiments were used to detect a potential target of Kur. Then, the p-chlorophenylalanine (PCPA) model was established in vivo to further study the effect of BACE1 expression on Kur and HNC. As a result, HNC viability was only significantly decreased by 2 μM of Kur. Kur reversed the impacts of corticosterone upon inhibiting viability (0.25-1 μM), PI3K (0.5-1 μM)/AKT phosphorylation, and BDNF (1 μM) level, and enhancing the apoptosis (0.25-1 μM) and BACE1 expression (1 μM) in HNCs. BACE1 was a potential target of Kur. Notably, Kur (150 mg/kg) attenuated PCPA-induced upregulation of BACE1 expression in rat hippocampal tissues as ZRAS (0.8 g/kg). The effects of Kur (1 μM) on corticosterone-treated HNCs were reversed by BACE1 overexpression. Collectively, Kur downregulates BACE1 level to activate PI3K/AKT, thereby attenuating corticosterone-induced toxicity in HNCs, indicating that Kur possibly exerted a neuroprotective effect, which providing a new perspective for the treatment of insomnia disorders.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/96/65/PRP2-11-e01132.PMC10517343.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacology Research & Perspectives","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/prp2.1132","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
The hippocampus has been implicated in the pathogenesis of insomnia disorder (ID) and the purpose of this study was to investigate the neuroprotective mechanism of the natural flavone Kurarinone (Kur) on hippocampal neurotoxicity as a potential treatment of ID. The effect of Kur on hippocampal neuronal cell (HNC) viability and apoptosis were assessed by Cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. Then, the effect of Kur on β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), brain-derived neurotrophic factor (BDNF), and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) phosphorylation level were measured by Western blot. Further, SwissTargetPrediction analysis and molecular docking experiments were used to detect a potential target of Kur. Then, the p-chlorophenylalanine (PCPA) model was established in vivo to further study the effect of BACE1 expression on Kur and HNC. As a result, HNC viability was only significantly decreased by 2 μM of Kur. Kur reversed the impacts of corticosterone upon inhibiting viability (0.25-1 μM), PI3K (0.5-1 μM)/AKT phosphorylation, and BDNF (1 μM) level, and enhancing the apoptosis (0.25-1 μM) and BACE1 expression (1 μM) in HNCs. BACE1 was a potential target of Kur. Notably, Kur (150 mg/kg) attenuated PCPA-induced upregulation of BACE1 expression in rat hippocampal tissues as ZRAS (0.8 g/kg). The effects of Kur (1 μM) on corticosterone-treated HNCs were reversed by BACE1 overexpression. Collectively, Kur downregulates BACE1 level to activate PI3K/AKT, thereby attenuating corticosterone-induced toxicity in HNCs, indicating that Kur possibly exerted a neuroprotective effect, which providing a new perspective for the treatment of insomnia disorders.
期刊介绍:
PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS