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: 10470285
• 负责人: Shaista Malik
• 金额: $ 66.25万
• 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/10470285
• 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); Data; Development; Diagnosis; Dorsal; Drops; Effectiveness; Electroacupuncture; Equilibrium; Goals; Human; Hypertension; Hypothalamic structure; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Lead; Measures; Mediating; Methods; Mind-Body Intervention; National Center for Complementary and Integrative Health; Nerve; Neural Pathways; Neuraxis; Neuroimmunomodulation; Neurons; Neurosecretory Systems; Outcome; Participant; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Rattus; Regulation; Research; Science; System; Therapeutic; Therapeutic Effect; Translating; Work; World Health Organization; base; blood pressure control; blood pressure reduction; cardiovascular risk factor; conventional therapy; cytokine; design; dorsal motor nucleus; experience; heart rate variability; hypertension control; hypertensive; immune function; improved; improved functioning; indexing; modifiable risk; neurobiological mechanism; neurophysiology; neuroregulation; paraventricular nucleus; peroneal nerve; randomized controlled study; 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。 抗高血压药物可以控制 HTN，但不能解决中枢交感神经和炎症通路，大约 50% 的高血压 (HTNive) 患者的血压 (BP) 无法得到控制。 世界卫生组织建议针灸治疗高血压；然而，之前使用针灸的临床试验显示出适度或无效的结果，并且没有实现具有临床意义的血压降低。这些相互矛盾的结果是由于缺乏基于机械的方法来使用电针（EA）（一种神经刺激形式）造成的。治疗和血压控制不充分的原因很复杂，但这种治疗失调的原因之一可能是对高血压发生和进展机制的不完全理解，包括自主神经功能障碍和由此产生的低度炎症。 利用神经解剖学绘图、表型分析和记录与 EA 潜在影响的神经调节机制相对应的神经生理反应，我们成功地选择了特定的穴位，这些穴位联合（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，而且改善了潜在的自主神经功能障碍 和低度炎症。 我们提出的研究解决了 NCCIH 的首要任务之一，“确定并分析针灸发挥治疗作用的神经通路。” 我们来自 Dahl 盐敏感 (DSS) HTNive 大鼠的强有力的初步数据表明，我们的靶向穴位同时激活正中神经、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) 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下降。 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。 我们的主要目的是评估 cEA 在 HTNive 动物中降低血压的作用机制，然后通过将其应用于轻度中度 HTNive 患者来验证自主神经指数的改善。 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，以及交感和副交感传出活动； 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) 在人类随机对照研究中使用平行 2x2 因子设计，主要评估 cEA 与假 EA 相比（其次比较交感抑制 EA、抗炎 EA 和 cEA）对自主神经功能生理改变的影响，其次评估对慢性炎症的影响。如果成功，这项研究将阐明 EA 作为治疗选择对仅用常规治疗无法达到最佳血压目标的 HTNive 患者的作用的机制基础。