Reversing anesthesia with Caffeine

用咖啡因逆转麻醉

• 批准号: 9322211
• 负责人: AARON P. FOX
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322211
• 关键词: Age; Amphetamines; Anesthesia procedures; Anesthetics; Animals; Arousal; Behavior; Blinded; Brain; Caffeine; Catecholamines; Chromaffin Cells; Clinical; Coma; Cyclic AMP; Depressed mood; Dopamine; Dopamine Receptor; Ephedra; Forskolin; General anesthetic drugs; Genetic; Goals; Grant; Hippocampus (Brain); Home environment; Hour; Human; Human Volunteers; Impaired cognition; In Vitro; Inpatients; Isoflurane; Knock-out; Learning; Literature; Mediating; Medicine; Membrane Lipids; Membrane Proteins; Methamphetamine; Methylphenidate; Mus; Neurobiology; Neurons; Neurotransmitters; Outpatients; PC12 Cells; Patients; Pharmaceutical Preparations; Pharmacology; Play; Property; Propofol; Purinergic P1 Receptors; Rattus; Receptor Activation; Recovery; Reporting; Reproducibility; Research; Role; Secretory Cell; Series; Signal Transduction; Site; Synapses; Synaptic plasticity; Testing; Theophylline; Thinking; Time; United States; Work; behavioral study; clinically relevant; cognitive ability; cognitive recovery; drug testing; extracellular; fluidity; inhibitor/antagonist; neurotransmitter release; public health relevance; receptor; synaptic function; ward

 DESCRIPTION (provided by applicant): The objective of this research is to determine whether caffeine reverses anesthesia in humans. General anesthetics induce a coma-like state; recovery from anesthesia is passive and is due to the discontinuation of anesthetic. Problematically, recovery from anesthesia is somewhat random, dependent upon a variety of factors like age or genetics that are beyond the clinician's control. Although "waking" from anesthesia can be relatively rapid, cognitive abilities are depressed for hours. In addition, some patients "wake" very slowly. It would be extremely beneficial to be able to time recovery from anesthesia in a reproducible manner and to have that recovery be complete. Our preliminary results, carried out in cultured PC12 cells and hippocampal neurons, suggested that general anesthetics inhibit neurotransmitter release. We hypothesized that inhibition of neurotransmitter release plays a key role in how anesthetics produce anesthesia in animals and humans. Furthermore we hypothesized that drugs that reverse the inhibitory effects of anesthetics on the release machinery should reverse anesthesia. Historically, cAMP signaling has been shown to play a key role in synaptic function and plasticity. Elevating cAMP facilitates neurotransmitter release. We posited that elevating intracellular cAMP might alter anesthetic action by restoring neurotransmitter release. Three drugs that elevate [cAMP]i levels, were tested; these drugs were found to completely reverse the inhibitory effects of anesthetics on neurotransmitter release in in vitro studies. When tested, these same cAMP elevating drugs dramatically accelerated recovery from anesthesia in rats. The most effective drug tested was caffeine which dramatically accelerated recovery from anesthesia (isoflurane and propofol) at relatively modest concentrations. In addition to elevating [cAMP]i, caffeine also inhibits adenosine receptors. A2A receptors mediate caffeine's arousal effects since knocking out this receptor or blocking it pharmacologically suppresses caffeine mediated arousal. It is possible that caffeine's ability to inhibit adenosine receptors helps it to reverse anesthesia. The goals of this application are: 1) Blinded Behavioral Studies in Mice and Rats - a) Determine whether A2A receptors play a role in reversing anesthesia. b) Determine whether caffeine works for all anesthetics. c) Determine optimal caffeine timing for anesthesia reversal. 2) Blinded Studies in Human Volunteers - a) Determine whether caffeine accelerates recovery from anesthesia and whether it accelerates recovery of cognitive abilities. b) Determine the optimal caffeine concentration and timing for anesthesia reversal. c) Determine whether caffeine is effective for all anesthetics. If caffeine accelerates recovery from anesthesia and restore cognitive abilities, then it may have the potential to impact medicine in a positive manner and in a brief time frame.

 描述（由申请人提供）：本研究的目的是确定咖啡因是否可以逆转人类的麻醉作用。全身麻醉会导致类似昏迷的状态；麻醉恢复是被动的，是由于麻醉的停止而导致的。问题是，从麻醉中恢复有些随机，取决于年龄或遗传等多种因素，这些因素超出了临床医生的控制范围。尽管从麻醉中“苏醒”的速度相对较快，但认知能力会下降数小时。此外，有些患者“醒来”的速度非常缓慢。能够以可重复的方式安排麻醉恢复时间并完全恢复将是非常有益的。我们在培养的 PC12 细胞和海马神经元中进行的初步结果表明，全身麻醉药会抑制神经递质的释放。我们假设抑制神经递质释放在麻醉剂如何对动物和人类产生麻醉作用中发挥着关键作用。此外，我们假设逆转麻醉剂对释放机制的抑制作用的药物应该逆转麻醉。从历史上看，cAMP 信号传导已被证明在突触功能和可塑性中发挥着关键作用。升高 cAMP 有助于神经递质的释放。我们假设升高细胞内 cAMP 可能通过恢复神经递质释放来改变麻醉作用。测试了三种提高 [cAMP]i 水平的药物；在体外研究中发现这些药物可以完全逆转麻醉剂对神经递质释放的抑制作用。经过测试，这些相同的 cAMP 升高药物显着加速了大鼠从麻醉中的恢复。所测试的最有效的药物是咖啡因，它在相对适中的浓度下可显着加速麻醉恢复（异氟烷和丙泊酚）。除了升高 [cAMP]i 之外，咖啡因还抑制腺苷受体。 A2A 受体介导咖啡因的兴奋作用，因为敲除该受体或在药理学上阻断它可以抑制咖啡因介导的兴奋。咖啡因抑制腺苷受体的能力可能有助于其逆转麻醉作用。该应用的目标是： 1) 小鼠和大鼠的盲法行为研究 - a) 确定 A2A 受体是否在逆转麻醉中发挥作用。 b) 确定咖啡因是否对所有麻醉剂都有效。 c) 确定麻醉逆转的最佳咖啡因时间。 2) 对人类志愿者进行盲法研究 - a) 确定咖啡因是否会加速麻醉恢复以及是否会加速认知能力的恢复。 b) 确定最佳咖啡因浓度和麻醉逆转时间。 c) 确定咖啡因是否对所有麻醉剂均有效。如果咖啡因能加速麻醉恢复并恢复认知能力，那么它可能有可能在短时间内以积极的方式影响医学。