Reversing anesthesia with Caffeine

用咖啡因逆转麻醉

• 批准号: 8948297
• 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/8948297
• 关键词: Age; Amphetamines; Anesthesia procedures; Anesthetics; Animals; Arousal; Behavior; Blinded; Brain; Caffeine; Catecholamines; Chromaffin Cells; 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; Nociception; Outpatients; PC12 Cells; Patients; Pharmaceutical Preparations; Play; Property; Propofol; Purinergic P1 Receptors; Rattus; Receptor Activation; Recovery; Reporting; Research; Role; Secretory Cell; Series; Signal Transduction; Site; Synapses; Synaptic plasticity; Testing; Theophylline; Thinking; Time; United States; Work; behavioral study; clinically relevant; cognitive ability; 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）：逆转这项研究的目的是确定咖啡因是否会逆转人类的麻醉状态；从麻醉中恢复是被动的，并且是由于麻醉的停止而导致的。麻醉在某种程度上是随机的，取决于临床医生无法控制的各种因素，例如年龄或遗传，尽管从麻醉中“醒来”可能相对较快，但认知能力会下降数小时。能够以可重复的方式确定麻醉恢复时间并使其完全恢复是非常有益的，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，全身麻醉剂会抑制。我们发现，神经递质释放的抑制在麻醉剂如何在动物和人类中产生麻醉作用中发挥着关键作用。此外，我们还开发出逆转麻醉剂对释放机制的抑制作用的药物。历史上，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，我们认为提高细胞内 cAMP 可能会通过恢复三种提高 [cAMP]i 水平的药物来改变麻醉作用。 ，经过测试；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。在测试中，这些相同的 cAMP 升高药物显着加速了恢复。相对测试的最有效的药物是咖啡因，它在适度浓度下可显着加速从麻醉中恢复，咖啡因除了提高[cAMP]i 之外，还抑制腺苷受体介导咖啡因的唤醒作用。敲除这种受体或通过药理学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逆转麻醉作用。是： 1) 小鼠和大鼠的盲法研究 - a) 确定 A2A 受体是否在逆转麻醉中发挥作用 b) 确定咖啡因是否适用于所有麻醉剂 c) 确定咖啡因逆转麻醉的最佳时机。人类志愿者 - a) 确定咖啡因是否加速麻醉恢复以及是否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。确定咖啡因是否对所有麻醉剂都有效。如果咖啡因能加速麻醉恢复并恢复认知能力，那么它可能会在短时间内以积极的方式影响医学。