Examination of a novel potential therapy for autonomic dysreflexia

研究一种治疗自主神经反射异常的新型潜在疗法

• 批准号: 10007106
• 负责人: Nadia Melanie Josephine Rupniak
• 金额: $ 39.48万
• 依托单位: DIGNIFY THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007106
• 关键词: Acute; Affect; Anatomy; Animal Model; Antiemetics; Autonomic Dysreflexia; Autonomic Nerve Block; Bladder; Blood Pressure; Cardiovascular Physiology; Cardiovascular system; Catheterization; Cell Nucleus; Cerebrum; Chronic; Clinical; Clinical Trials; Data; Dose; Event; FDA approved; Female; Fiber; Functional disorder; Future; Goals; Hypertension; Hypertensive Crisis; Individual; Injury; Interruption; Intestines; Life; Medical emergency; Modeling; Monitor; Neurons; Neurotransmitters; Organ; Pathway interactions; Pelvis; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiological; Prevention; Prevention trial; Procedures; Rattus; Reflex action; Reporting; Rest; Safety; Sensory; Severities; Small Business Technology Transfer Research; Spinal; Spinal cord injury; Stimulus; Structure; Substance P; Synaptic plasticity; Telemetry; Testing; Vasomotor; Viscera; Visceral; colorectal distension; dorsal horn; drug candidate; experience; male; novel; novel therapeutic intervention; pre-clinical; prevent; programs; receptor; sensory stimulus; spinal reflex

PROJECT SUMMARY/ABSTRACT Autonomic dysreflexia (AD) is a potentially life-threatening hypertensive crisis that predominantly affects individuals with a spinal cord injury (SCI) above T6. AD can be triggered idiopathically or by distention or manipulation of pelvic visceral organs, especially the bladder and bowel, which can occur with catheterization and fecal evacuation procedures that are necessary to manage bladder and bowel emptying. Sensory stimuli arising from the pelvic viscera activate cardiovascular sympathetic preganglionic neurons through an intersegmental spinal reflex that triggers AD. Currently, there are no pharmaceutical agents approved for the prevention of AD. A potential novel therapeutic approach may be to use an antagonist that inhibits a receptor (that is anatomically, physiologically, pharmacologically, and clinically implicated in the spinal control of visceral and cardiovascular function at various points in the reflex pathways responsible for AD) to prevent the occurrence of AD. Our preliminary data indicate that blocking the actions of a specific endogenous neurotransmitter using a selective receptor antagonist inhibits colorectal distension (CRD)-induced hypertension in anesthetized rats with acute SCI. We hypothesize that selective antagonists of this receptor will also reduce or eliminate hypertension induced by CRD in rats with chronic SCI, and that the effect may be greater after a chronic injury because of synaptic plasticity changes and sprouting of fibers in the L6 dorsal horn and sacral parasympathetic nucleus. This hypothesis will be tested by examining the ability of selective antagonists to block AD induced by CRD, and spontaneous AD events, in rats with chronic SCI. In Specific Aim 1, we will examine the effects of antagonists on CRD-induced hypertension in male and female rats with chronic SCI. In Specific Aim 2, we will select the most efficacious antagonist from Aim 1 to determine the effect of daily SC administration for 1 week on resting blood pressure and spontaneous AD events in rats with chronic SCI. As several selective antagonists are approved for clinical use in the US, it is reasonable to expect that a proof of concept clinical trial for the prevention of AD could begin soon after obtaining supportive data from this proposal.

项目总结/摘要 自主神经反射异常（AD）是一种潜在的危及生命的高血压危象， 主要影响T6以上脊髓损伤（SCI）的个体。AD可以是 特发性或由盆腔内脏器官的膨胀或操作引发， 特别是膀胱和肠道，这可能会发生导管插入和粪便 排空程序是管理膀胱和肠道排空所必需的。 来自盆腔内脏的感觉刺激激活心血管交感神经 神经节前神经元通过节段间脊髓反射触发AD。 目前，没有批准用于预防AD的药剂。 一种潜在的新的治疗方法可以是使用一种拮抗剂，该拮抗剂可以抑制肿瘤细胞的增殖。 受体（即在解剖学、生理学、生物学和临床上 在不同的时间点与内脏和心血管功能的脊髓控制有关， 负责AD的反射途径），以防止AD的发生。 我们的初步数据表明，阻断特定内源性 使用选择性受体拮抗剂的神经递质抑制结肠直肠扩张 （CRD）诱导的急性SCI麻醉大鼠高血压。我们假设 该受体的选择性拮抗剂也将减少或消除由高血压引起的 CRD在慢性SCI大鼠中的作用，并且在慢性损伤后效果可能更大 由于突触可塑性变化和L 6背角纤维的发芽， 骶副交感神经核这一假设将通过检查 选择性拮抗剂阻断CRD诱导的AD和自发AD事件， 慢性SCI大鼠在具体目标1中，我们将研究拮抗剂对 慢性SCI雄性和雌性大鼠中CRD诱导的高血压。 在具体目标2中，我们将从目标1中选择最有效的拮抗剂，以确定 每日SC给药1周对静息血压的影响， 慢性SCI大鼠自发性AD事件。 由于几种选择性拮抗剂在美国已被批准用于临床， 预计预防AD的概念验证临床试验将很快开始 在从该提案中获得支持性数据后。