Neuroimmune mechanisms underlying electroacupuncture effect on vascular function

电针影响血管功能的神经免疫机制

基本信息

批准号：
10693901
负责人：
Shaista Malik
金额：
$ 64.42万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693901
关键词：
Acupuncture Points Acupuncture Therapy Address Age Aging Animals Anti-Inflammatory Agents Antihypertensive Agents Area Autonomic Dysfunction Autonomic nervous system Biological Markers Blood Pressure Blood Vessels Brain Stem Cardiovascular Diseases Cell Nucleus Central Nervous System Chronic Clinical Clinical Research Clinical Trials Complex Data Development Diagnosis Dorsal Drops Effectiveness Electroacupuncture Equilibrium Goals Human Hypertension Hypothalamic structure Immune system Inflammation Inflammation Mediators Inflammatory Maps Measures Mediating Methods National Center for Complementary and Integrative Health Nerve Neural Pathways Neuroanatomy Neuroimmunomodulation Neurons Neurosecretory Systems Outcome Participant Pathway interactions Patients Peripheral Phenotype Physiological Qualifying Rattus Regulation Research Science Structure of tibial nerve System Therapeutic Therapeutic Effect Translating Work World Health Organization alpha-bungarotoxin receptor blood pressure control blood pressure reduction cardiovascular risk factor conventional therapy cytokine design dorsal motor nucleus experience functional improvement heart rate variability human old age (65+)hypertension control hypertensive immune function improved indexing mind/body modifiable risk neural neurobiological mechanism neurophysiology neuroregulation paraventricular nucleus peroneal nerve randomized, controlled study receptor response salt sensitive somatosensory study population

项目摘要

PROJECT SUMMARY Hypertension (HTN) is the most significant modifiable risk factor for cardiovascular disease and involves multiple pathways including those in the neuroendocrine and immune systems. Antihypertensive drugs manage HTN but do not address the central sympathetic and inflammatory pathways and approximately 50% of hypertensive (HTNive) patients do not have their blood pressure (BP) controlled. The World Health Organization has suggested acupuncture for HTN; however, prior clinical trials utilizing acupuncture have shown modest or null outcomes and not achieved clinically meaningful reductions in BP. These conflicting outcomes result from the lack of a mechanistic-based approach to using electroacupuncture (EA), a form of neurostimulation. The reasons for inadequate treatment and BP control are complex, but one reason for this therapeutic misalignment may be an incomplete understanding of the mechanisms underlying the development and progression of HTN including autonomic dysfunction and resulting low-grade inflammation. Using neuroanatomical mapping, phenotyping, and recording of neurophysiological responses that correspond to neuromodulatory mechanisms underlying effects of EA, we successfully selected specific acupoints that in combination (or combined (c)EA) show complementary mechanisms of sympathoinhibition and parasympathoexcitation and not only reduce BP to clinically meaningful levels but also improve underlying autonomic dysfunction and low-grade inflammation. Our proposed study addresses one of NCCIH’s top priorities, “Determine and analyze the neural pathways by which acupuncture exerts its therapeutic effects.” Our strong preliminary data, from Dahl Salt Sensitive (DSS) HTNive rats, show that our targeted acupoints, which simultaneously activate afferents in the median, tibial, and deep peroneal nerves then modulate CNS regulation by activation of neurons in the nucleus of tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMV). This modulation resulted in an increase in descending peripheral parasympathetic splenic activity. Treatment with cEA also reduced presympathetic neuronal and splanchnic sympathetic nerve activities. In this study, we will investigate if cEA treatment leads to BP reduction by improving autonomic dysfunction and decreasing inflammation through the neural mechanistic pathways we have preliminarily discovered. Our main aim is to assess mechanisms of the BP lowering effect of cEA in HTNive animals and then validate the improvement in autonomic indices by translating it in mild-moderative HTNive patients. We plan to achieve this by: 1) direct assessment of the effect of cEA on neurons in the hypothalamic and brainstem regions controlling sympathetic and parasympathetic balance including NTS, DMV, paraventricular nucleus, and rostral ventrolateral medulla, as well as sympathetic and parasympathetic efferent activities; 2) investigating if cEA reduces inflammation through acetylcholinergic receptors (AChR) activity in DSS HTNive rats; and 3) using a parallel 2x2 factorial design in a human randomized control study, primarily assess effects of cEA compared to sham-EA (as well as secondarily compare sympathoinhibitory-EA, anti-inflammatory-EA, and cEA) on physiological alterations in autonomic function and secondarily on chronic inflammation. If successful, this study would address the mechanistic basis for the effects of EA as a therapeutic option for HTNive patients who are not at optimal BP goals with conventional therapy alone.

项目概要高血压 (HTN) 是心血管疾病最重要的可改变危险因素，涉及多种途径，包括神经内分泌和免疫系统中的途径，抗高血压药物可控制 HTN，但不能解决中枢交感神经和炎症途径以及约 50% 的高血压 (HTNive)。世界卫生组织建议针灸治疗高血压患者；然而，之前使用针灸的临床试验显示效果有限或无效，并且没有取得临床意义。这些相互矛盾的结果是由于缺乏使用电针（EA）（一种神经刺激形式）的机械方法造成的。治疗和血压控制不充分的原因很复杂，但造成这种治疗失调的一个原因可能是。对 HTN 发生和进展的机制的不完全了解，包括自主神经功能障碍和由此产生的低度炎症，使用神经解剖学定位、表型分析和记录与 HTN 影响的神经调节机制相对应的神经生理反应。 EA，我们成功地选择了特定的穴位，这些穴位组合（或组合（c）EA）显示出交感抑制和副交感兴奋的互补机制，不仅将血压降低到有临床意义的水平，而且还改善了潜在的自主神经功能障碍和低度炎症。 NCCIH 的首要任务之一是“确定并分析针灸发挥治疗作用的神经通路。”我们来自 Dahl Salt Sensitive (DSS) 的强有力的初步数据。 HTNive 大鼠表明，我们的靶向穴位可同时激活正中神经、胫神经和腓深神经的传入神经，然后通过激活孤束核 (NTS) 和迷走神经背运动核 (DMV) 中的神经元来调节 CNS 调节这种调节导致外周副交感神经脾脏活动增加，cEA 治疗还减少了交感前神经元和内脏交感神经的活动。在这项研究中，我们将研究 cEA 治疗是否通过我们初步发现的神经机制途径改善自主神经功能障碍和减少炎症来降低血压。我们计划通过以下方式实现这一目标：1）直接评估 cEA 对下丘脑和脑干区域神经元的影响。控制交感神经和副交感神经平衡，包括 NTS、DMV、室旁核和头端腹外侧延髓，以及交感神经和副交感神经传出活动；2) 研究 cEA 是否通过 DSS HTNive 大鼠的乙酰胆碱能受体 (AChR) 活性减轻炎症；3) 使用人类随机对照研究中的平行 2x2 因子设计，主要评估 cEA 与假 EA 相比的效果（以及其次比较交感抑制型 EA、抗炎型 EA 和 cEA）对自主神经功能的生理变化以及其次对慢性炎症的影响，如果成功，这项研究将解决 EA 作为治疗选择的作用的机制基础。适用于仅采用常规治疗未达到最佳血压目标的 HTNive 患者。