Mechanistic insights into the neuroprotective effects of low-intensity transcranial ultrasound stimulation in post-cardiac arrest brain injury: Modulation of the Piezo1-Dkk3/PI3K-Akt pathway

IF 8.8 2区 医学 Q1 IMMUNOLOGY
Shuang Xu , Lulu Gu , Banghe Bao , Qian Liu , Qiaofeng Jin , Yannan Ma , Siyi Zhou , Beibei Li , Li Xu , Guangqi Guo , Jinpiao Zhu , Kuan-Pin Su , Peng Sun
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Abstract

Post-cardiac arrest brain injury (PCABI) remains a significant challenge, marked by high mortality and disability rates due to persistent neuroinflammation. This study explored the neuroprotective potential of low-intensity transcranial ultrasound stimulation (LITUS) in mitigating brain damage after cardiopulmonary resuscitation (CPR) using a murine model and in vitro assays. LITUS treatment improved 24-h survival rates and neurological recovery in cardiac arrest (CA) mice, as evidenced by behavioral assessments and reduced neurological deficit scores. Proteomic analyses revealed modulation of Piezo1-Dkk3/PI3K-Akt signaling pathway, characterized by decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Mechanistic studies demonstrated that LITUS enhanced Piezo1 and Dkk3 activation, promoting calcium influx and anti-inflammatory responses. The Piezo1 antagonist GsMTx4 abrogated these effects, underscoring Piezo1’s specific role. Additionally, in vitro experiments using oxygen/glucose deprivation and reoxygenation (OGD/R)-treated BV2 microglial cells confirmed that LITUS reduced inflammatory responses and enhanced cellular recovery via the Piezo1-Dkk3 axis. These findings highlight LITUS as a promising non-invasive therapeutic strategy to ameliorate PCABI by modulating neuroinflammation through the Piezo1-Dkk3/PI3K-Akt pathway. This work provides a basis for translational research and potential clinical applications in improving outcomes for CPR survivors.
低强度经颅超声刺激对心脏骤停后脑损伤神经保护作用的机制研究:Piezo1-Dkk3/PI3K-Akt通路的调节
心脏骤停后脑损伤(PCABI)仍然是一个重大挑战,其特点是由于持续的神经炎症导致的高死亡率和致残率。本研究通过小鼠模型和体外实验探讨了低强度经颅超声刺激(LITUS)在减轻心肺复苏(CPR)后脑损伤方面的神经保护潜力。LITUS治疗提高了心脏骤停(CA)小鼠的24小时存活率和神经系统恢复,行为评估和降低神经功能缺陷评分证明了这一点。蛋白质组学分析显示Piezo1-Dkk3/PI3K-Akt信号通路的调节,其特征是促炎细胞因子(IL-1β, IL-6, TNF-α)的降低。机制研究表明,LITUS增强Piezo1和Dkk3的激活,促进钙内流和抗炎反应。Piezo1拮抗剂GsMTx4消除了这些作用,强调了Piezo1的特殊作用。此外,体外氧/葡萄糖剥夺和再氧化(OGD/R)处理的BV2小胶质细胞实验证实,LITUS通过Piezo1-Dkk3轴减少炎症反应并增强细胞恢复。这些发现强调了LITUS是一种很有前途的非侵入性治疗策略,可以通过Piezo1-Dkk3/PI3K-Akt通路调节神经炎症来改善PCABI。这项工作为转化研究和潜在的临床应用提供了基础,以改善心肺复苏术幸存者的预后。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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