Kurarinone通过靶向BACE1激活P13K-AKT信号对皮质酮诱导的大鼠海马神经元细胞毒性的神经保护作用——失眠障碍的潜在治疗方法。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Guoqing Wu, Yanyan Wu
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引用次数: 0

摘要

海马与失眠障碍(ID)的发病机制有关,本研究的目的是探讨天然黄酮Kurarinone(Kur)对海马神经毒性的神经保护机制,作为治疗ID的潜在药物。分别通过细胞计数试剂盒-8(CCK-8)法和流式细胞术评估Kur对海马神经元细胞(HNC)活力和凋亡的影响。然后,通过蛋白质印迹法测定Kur对β-位点淀粉样蛋白前体蛋白裂解酶1(BACE1)、脑源性神经营养因子(BDNF)和磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(AKT)磷酸化水平的影响。此外,SwissTargetPrediction分析和分子对接实验被用于检测Kur的潜在目标。然后,在体内建立对氯苯丙氨酸(PCPA)模型,进一步研究BACE1表达对Kur和HNC的影响。结果,HNC活力仅显著降低2 μM的Kur。Kur逆转皮质酮对抑制生存能力的影响(0.25-1 μM),PI3K(0.5-1 μM)/AKT磷酸化和BDNF(1 μM)水平,并增强细胞凋亡(0.25-1 μM)和BACE1表达(1 μM)。BACE1是Kur的潜在靶点。值得注意的是,库尔(150 mg/kg)作为ZRAS(0.8 g/kg)。库尔(1 μM)通过BACE1过表达逆转。总之,Kur下调BACE1水平以激活PI3K/AKT,从而减轻皮质酮诱导的HNCs毒性,表明Kur可能发挥神经保护作用,这为治疗失眠障碍提供了新的视角。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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.

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.

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.

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.

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.

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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
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
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