Neuroimmune mechanisms underlying electroacupuncture effect on vascular function

电针影响血管功能的神经免疫机制

• 批准号: 10316925
• 负责人: Shaista Malik
• 金额: $ 67.99万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/10316925
• 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; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Conflict (Psychology); Crossover Design; Dahl Hypertensive Rats; Data; Development; Diagnosis; Dorsal; Drops; Effectiveness; Electroacupuncture; Equilibrium; Goals; Human; Hypertension; Hypothalamic structure; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Lead; Maintenance; Measures; Mediating; Mind-Body Intervention; Nerve; Neural Pathways; Neuraxis; Neuroimmunomodulation; Neurons; Neurosecretory Systems; Outcome; Participant; Pathway interactions; Patients; Peripheral; Phenotype; Physiologic pulse; Physiological; Randomized; Rattus; Regulation; Research; Science; System; Therapeutic; Therapeutic Effect; Translating; Vascular Endothelium; Work; World Health Organization; arterial stiffness; base; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; conventional therapy; cytokine; design; dorsal motor nucleus; endothelial dysfunction; experience; hypertension control; improved; improved functioning; indexing; modifiable risk; neurobiological mechanism; neurophysiology; neuroregulation; paraventricular nucleus; peroneal nerve; receptor; relating to nervous system; response; salt sensitive; somatosensory; study population

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.

项目摘要 高血压（HTN）是心血管疾病的最显着修改风险因素，涉及多种途径，包括神经内分泌和免疫系统中的途径。降压药管理HTN，但不能解决中心交感神经和炎症途径，大约50％的高血压（HTNIVE）患者没有控制其血压（BP）。世界卫生组织建议HTN针灸。但是，使用针灸的先前临床试验显示出适度或无效的结果，并且在BP中没有实现临床意义的减少。这些相互矛盾的结果是由于缺乏使用电针（EA）的一种基于机械的方法，一种神经刺激的形式。治疗和BP控制不足的原因很复杂，但是这种治疗性错位的原因之一可能是对HTN发育和进展的机制不完全理解，包括自主性功能障碍和导致低级炎症。使用与EA的神经调节机制相对应的神经生理反应的神经解剖学，表型和记录，我们成功选择了组合（或组合（C）EA组合（C）EA的完整机制的交感神经和副作用的临床，我们成功选择了结合（或组合（C）EA的组合（COMBOLINED（C））低度感染。我们提出的研究介绍了NCCIH的首要任务之一，“确定和分析针灸会执行其治疗作用的神经途径。”我们来自DAHL盐灵敏（DSS）HTNIVE大鼠的强大初步数据表明，我们的靶向穴位简单地激活了中位数，胫骨和深peroneal神经中的传入，然后通过激活Tractus Solidarius solidarius（NTS）的神经元激活神经元来调节CNS调节，该神经元（NTS），dorsal motileus（dorsal motileus dag dag dag dag dag dag dag dag dag dag）该调节导致外围副交感神经活性下降。 CEA治疗还减少了交感神经元和方案交感神经活动。在这项研究中，我们将调查CEA治疗是否通过改善自主神经功能障碍并通过我们最初发现的神经元机械途径减少感染来减少BP。我们的主要目的是评估CEA在HTNIVE动物中降低BP降低作用的机制，然后通过将其转换为轻度调节性HTNIVE患者，从而验证自主指数的改善。我们计划通过：1）直接评估CEA对下丘脑和脑干区域中控制交感神经和副交感神经平衡的影响，包括NTS，DMV，DMV，旁腔室核和thostral腹侧髓质，以及交感神经和交感神经会和副pathsodysctasextic的有效活性； 2）研究CEA是否通过DSS HTNIVE大鼠中的乙酰胆碱能受体（ACHR）活性降低感染； 3）在人类随机对照研究中使用平行的2x2阶乘设计，与Sham-AEA相比，CEA的主要评估影响（以及次级比较交感神经EA，抗炎 - EA和CEA）对自主功能的生理变化和次要对慢性感染的生理变化。如果成功的话，这项研究将针对EA作为治疗选择的机械基础，对于不采用常规治疗的最佳BP目标的HTNIVE患者的治疗选择。