Reversing anesthesia with Caffeine

 描述（由申请人提供）：本研究的目的是确定咖啡因是否逆转人体麻醉。全身麻醉药引起昏迷样状态;从麻醉中恢复是被动的，是由于停止麻醉。问题是，从麻醉中恢复是随机的，取决于各种因素，如年龄或遗传学，这些因素超出了临床医生的控制。虽然从麻醉中“醒来”可能相对较快，但认知能力会被抑制数小时。此外，有些患者“醒来”非常缓慢。能够以可再现的方式确定从麻醉中恢复的时间并使该恢复完全将是极其有益的。我们在培养的PC 12细胞和海马神经元中进行的初步结果表明，全身麻醉药抑制神经递质的释放。我们假设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中起着关键作用。此外，我们假设，药物逆转麻醉药的抑制作用的释放机制应该逆转麻醉。从历史上看，cAMP信号传导已被证明在突触功能和可塑性中起关键作用。升高cAMP促进神经递质释放。我们推测，升高细胞内cAMP可能通过恢复神经递质释放而改变麻醉作用。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完全逆转了麻醉剂对神经递质释放的抑制作用。当测试时，这些相同的cAMP升高药物显着加速大鼠从麻醉中恢复。最有效的药物测试是咖啡因，显着加速从麻醉（异氟烷和丙泊酚）在相对温和的浓度恢复。除了升高[cAMP]i，咖啡因还抑制腺苷受体。A2 A受体介导咖啡因的唤醒作用，因为敲除或阻断这种受体会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它逆转麻醉。本申请的目标是：1）小鼠和大鼠的盲法行为研究- a）确定A2 A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）确定咖啡因逆转麻醉的最佳时间。2)在人类志愿者中进行的盲法研究- 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。c）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。

 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.