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（由适用提供）：这项研究的目的是确定咖啡因是否会逆转人类麻醉。通用麻醉剂会引起昏迷状态；从麻醉中恢复是被动的，是由于麻醉的停用。在问题上，从麻醉中恢复有些随机，取决于多种因素或遗传学超出临床控制的因素。尽管从麻醉中“醒来”可能相对较快，但认知能力抑制了几个小时。此外，一些患者“唤醒”非常缓慢。能够以可复制的方式从麻醉中恢复并完成恢复是非常有益的。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，普通麻醉剂抑制神经递质释放。我们假设抑制神经递质释放在麻醉药如何在动物和人类中进行麻醉方面起着关键作用。此外，我们假设扭转麻醉药对释放机械的抑制作用的药物应逆转麻醉。从历史上看，cAMP信号已被证明在突触功能和可塑性中起关键作用。抬高营地有助于神经递质的释放。我们肯定的是，升高细胞内cAMP可能会通过恢复神经递质释放来改变麻醉作用。测试了三种升高[CAMP] I水平的药物；发现这些药物在体外研究中完全扭转了麻醉药对神经递质释放的抑制作用。经过测试时，这些相同的营地升高药物在大鼠的麻醉中急剧加速了恢复。最有效的药物测试是咖啡因，它在相关较小的浓度下从麻醉（异氟烷和建议）中急剧加速了康复。除了升高[CAMP] I外，咖啡因还抑制腺苷受体。 A2A受体介导咖啡因的唤醒作用以来，击倒了该受体或阻塞IT可以抑制咖啡因介导的唤醒。咖啡因抑制腺苷受体的能力可能有助于其逆转麻醉。该应用的目标是：1）在小鼠和大鼠中盲目的行为研究 - a）确定A2A受体是否在逆转麻醉中起作用。 b）确定咖啡因是否适用于所有麻醉逆转。 c）确定麻醉逆转的最佳咖啡因时间。 2）在人类志愿者中盲目的研究 - a）确定咖啡因是否会加速从麻醉中恢复，以及它是否会加速认知能力的恢复。 b）确定麻醉逆转的最佳咖啡因浓度和时间。 c）确定咖啡因是否对所有麻醉剂有效。如果咖啡因可以加速从麻醉中恢复并恢复认知能力，那么它可能有可能以积极的方式和短暂的时间范围影响医学。