Mechanisms of MDMA-induced hyperthermia

MDMA 引起的高热机制

• 批准号: 7297902
• 负责人: Edward M Mills
• 金额: $ 22.15万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7297902
• 关键词: Abuse Reporting; Acute; Address; Adipose tissue; Adult; Adverse effects; Affinity; Anatomy; Animal Model; Animals; Antidotes; Area; Biology; Blood Circulation; Blood Coagulation Disorders; Body Temperature; Brain Injuries; Breeding; Brown Fat; Cardiovascular system; Carnitine; Cell membrane; Cessation of life; Chemosensitization; Chronic; Clinical Research; Condition; Crossbreeding; Data; Development; Diabetes Mellitus; Diet; Disseminated Intravascular Coagulation; Dose; Drug Delivery Systems; Engineering; Fatty Acids; Fatty acid glycerol esters; Fever; Generations; Genetic; Goals; Heat Losses; Heating; Homeostasis; Homologous Gene; Hormones; Human; Hyperthyroidism; Hypothalamic structure; In Situ; In Vitro; Induced Hyperthermia; Infection; Intoxication; Knockout Mice; Life; Ligands; Link; Lipopolysaccharides; Literature; Mammals; Measures; Mediating; Mediator of activation protein; Medicine; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Muscle; Muscle Proteins; Muscle function; NIH Program Announcements; Nematoda; Nonesterified Fatty Acids; Obesity; Organ; Organ failure; Outcome Study; Overdose; Palmitoyl Coenzyme A; Pathologic; Pathology; Pathway interactions; Peripheral; Physiologic Thermoregulation; Physiological; Plants; Plasma; Play; Proteins; Protons; Public Health; Publishing; Pyrogens; Range; Research; Resolution; Rodent; Role; Second Messenger Systems; Shivering; Signal Transduction; Site; Skeletal Muscle; Skeletal system; Stimulus; Temperature; Testing; Therapeutic Intervention; Thermogenesis; Thinking; Time; Tissues; Transgenes; Triglycerides; United Nations; Vasodilation; Vertebrates; Wild Type Mouse; Work; base; day; drug of abuse; ecstasy; etomoxir; feeding; fly; hyperthermia treatment; in vivo; insight; medical complication; mitochondrial uncoupling protein 3; neurotoxicity; novel; prevent; prototype; psychostimulant; response; second messenger; stem; transport inhibitor; uncoupling protein 1; uptake; vasoconstriction

DESCRIPTION (provided by applicant): Work in this proposal addresses the Program Announcement (PA-06-525) entitled "MDMA: Research Areas Needing More Emphasis (R21)". The most dangerous side effect of acute MDMA intoxication is hyperthermia, a hyper-metabolic condition that stems from a dramatic increase in "non-shivering" metabolic thermogenesis in the setting of heat conservation (peripheral vasoconstriction). MDMA-induced hyperthermia leads to a cascade of life threatening medical complications including skeletal muscle breakdown, cardiovascular collapse, multi-organ failure, and disseminated intravascular coagulation. In animals, hyperthermia also strongly potentiates long term neurotoxicity. No treatment exists for the reversal of hyperthermia induced by MDMA and related compounds, most likely because the direct mediators of human thermogenesis in response to normal (cold, feeding, infection) and pathologic (MDMA, endocrinopathies) thermogenic stimuli have not been identified. Uncoupling proteins (UCPs) are highly conserved thermogenic molecules that regulate mitochondrial heat production in plants, nematodes, flies, and vertebrates. In mammals, brown fat UCP1 is thought to be the dominant, if not the only significant mediator of thermogenic responses. Arguing strongly against this is the fact that adult humans express negligible amounts of brown fat and UCP1, yet do show significant non-shivering thermogenic responses (i.e. MDMA hyperthermia, diet induced thermogenesis, fever). Skeletal muscle is the most important thermogenic organ in humans, and a major target of MDMA-induced pathology; thus, we reasoned that the recently identified uncoupling protein 3, expressed primarily in skeletal muscle (UCP3) may mediate MDMA hyperthermia. We tested this in mice lacking UCP3. UCP3 knockout mice have a near complete loss (~80%) of MDMA-induced thermogenesis and are completely protected from MDMA-induced death over a range of lethal doses. Consistent with the general thermoregulatory relevance of UCP3 in inducible thermogenesis, we also observed that UCP3 knockout mice lose the capacity to generate a fever in response to the bacterial pyrogen lipopolysaccharide. With regard to mechanisms of UCP3 activation, we observed that free fatty acids - required ligands for UCP3 function in vitro - are elevated in the bloodstream prior to peak MDMA-induced hyperthermia. Additionally, we found that high fat feeding increases levels of plasma free fatty acids and correspondingly potentiates MDMA hyperthermia. The overall goal of this proposal is to identify the tissue target(s) and mechanisms involved in MDMA-induced UCP3-dependent thermogenesis. Specific Aim #1: To identify the target tissue of UCP3-dependent thermogenesis. Specific Aim #2: To characterize the role of free fatty acids in UCP3 activation by MDMA in vivo. Together, these studies will significantly advance our mechanistic understanding of this novel, UCP3-dependent thermogenic pathway in humans and may reveal novel drug targets for the treatment of a range of thermoregulatory illnesses ranging from hyperthermia to obesity and diabetes. Work in this proposal addresses the program announcement PA-06-525, entitled "MDMA: Research Areas Needing More Emphasis". One of the most widely abused drugs in the world, MDMA overdose can give rise to fatal hyperthermia. No treatment exists for MDMA hyperthermia. Work in this proposal aims to determine where in the body heat generation occurs after MDMA treatment in animals, and the molecules that are involved in generating the heat response. It is expected that this work will provide a rational basis for the development of the first effective hyperthermia medicine able to directly turn off heat production.

描述（由申请人提供）：本提案中的工作涉及题为“MDMA：需要更多强调的研究领域（R21）”的项目公告（PA-06-525）。急性MDMA中毒最危险的副作用是高热，这是一种高代谢状态，源于热保存（外周血管收缩）下“非颤抖”代谢性产热的急剧增加。mdma诱导的高温可导致一系列危及生命的并发症，包括骨骼肌衰竭、心血管衰竭、多器官衰竭和弥散性血管内凝血。在动物中，高温也会增强长期的神经毒性。目前还没有治疗方法可以逆转MDMA和相关化合物引起的高热，很可能是因为人体对正常（寒冷、喂养、感染）和病理（MDMA、内分泌疾病）热刺激的直接产热介质尚未确定。解偶联蛋白（Uncoupling protein, UCPs）是高度保守的产热分子，在植物、线虫、苍蝇和脊椎动物中调节线粒体产热。在哺乳动物中，棕色脂肪UCP1被认为是产热反应的主要媒介，如果不是唯一的重要媒介。强烈反对这一观点的事实是，成年人表达的棕色脂肪和UCP1的数量可以忽略不计，但确实表现出显著的非颤抖产热反应（即MDMA热休克、饮食诱导产热、发烧）。骨骼肌是人体最重要的产热器官，也是mdma诱导病理的主要靶点；因此，我们推断，最近发现的主要在骨骼肌中表达的解偶联蛋白3 （UCP3）可能介导MDMA高温。我们在缺乏UCP3的小鼠中进行了测试。UCP3敲除小鼠几乎完全丧失（~80%）mdma诱导的产热作用，并且在一定致死剂量范围内完全免受mdma诱导的死亡。与UCP3在诱导产热中的一般热调节相关性一致，我们还观察到UCP3敲除小鼠在对细菌热原脂多糖的反应中失去了发热的能力。关于UCP3激活的机制，我们观察到游离脂肪酸——体外UCP3功能所需的配体——在mdma诱导的高温达到峰值之前在血液中升高。此外，我们发现高脂肪喂养会增加血浆游离脂肪酸水平，并相应地增强MDMA热疗。本提案的总体目标是确定mdma诱导的ucp3依赖性产热的组织靶点和机制。特异性目的1：确定ucp3依赖性产热作用的靶组织。具体目标2：表征游离脂肪酸在体内MDMA活化UCP3中的作用。总之，这些研究将显著推进我们对这种新的、依赖ucp3的人类产热途径的机制理解，并可能揭示新的药物靶点，用于治疗从高温到肥胖和糖尿病等一系列热调节性疾病。本提案中的工作涉及项目公告PA-06-525，题为“MDMA：需要更多重视的研究领域”。MDMA是世界上滥用最广泛的药物之一，过量服用会导致致命的高热。没有治疗MDMA热疗的方法。本提案的工作旨在确定MDMA治疗后动物体内产生热量的位置，以及参与产生热反应的分子。期望这项工作将为开发第一种能够直接关闭热量产生的有效热疗药物提供合理的基础。