Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke - Preclinical experience
Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke - Preclinical experience
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DOI：
10.1161/01.str.0000068170.80517.b3
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发表时间：
2003-05-01
期刊：
影响因子：
8.3
通讯作者：
Grotta, JC
中科院分区：
文献类型：
--
作者：
Aronowski, J;Strong, R;Grotta, JC
背景和目的-乙醇和咖啡因是两种常见的精神活性饮食成分。我们最近发现，在可逆性颈总动脉/大脑中动脉（CCA/MCA）闭塞后，低剂量乙醇加咖啡因可使大鼠梗死体积减少70%至80%。在中风发作后2小时内，口服预处理或静脉给药后，联合用药（咖啡醇）均有效。单独使用乙醇会加剧缺血性损伤，而单独使用咖啡因则没有影响。缺血前2周每日咖啡因醇消除了急性治疗（耐受性）中观察到的神经保护作用。我们目前的研究的目的是进一步表征咖啡醇作为一种可能的治疗缺血性stroks. Methods短暂的CCA/MCA闭塞模型的属性被用于所有的实验。进行了五组实验（1）以测试各种剂量的乙醇的有效性（0.2至0.65克/公斤）和咖啡因（2）测试咖啡醇的神经保护剂量是否可以改善行为功能障碍;（3）测试缺血前的慢性乙醇或咖啡因是否会影响咖啡醇治疗的功效;（4）检测咖啡醇与35 ℃低温联合应用是否能提高咖啡醇的保护作用;（5）在缺血动物中测试咖啡醇是否影响施用重组组织纤溶酶原激活剂（rtPA）后的出血频率。在短暂的CCA/MCA闭塞后，咖啡因醇中的咖啡因kg可有效减少皮质梗死体积和行为功能障碍。在CCA/MCA闭塞之前每日暴露于乙醇而不是咖啡因消除了急性咖啡醇治疗的治疗效果，类似于慢性暴露于咖啡醇后观察到的耐受性。咖啡因醇的治疗效果可以通过与轻度缺血内低温配对来进一步改善，并且咖啡因醇与rtPA. Conclusions联合给药时不会增加出血性梗死，低剂量的咖啡因醇，相当于不超过2至3杯浓咖啡和1杯鸡尾酒，具有一致的高度神经保护作用，耐受性良好，可以添加到其他疗法中以增加每种疗法的效果，并且不干扰rtPA治疗或使其复杂化。咖啡因醇是中风患者临床试验的合适候选药物，尽管它在经常饮酒的患者中可能不太有效。
Background and Purpose-Ethanol and caffeine are 2 common psychoactive dietary components. We have recently shown that low-dose ethanol plus caffeine results in a 70% to 80% reduction of infarct volume after reversible common carotid/middle cerebral artery (CCA/MCA) occlusion in rats. The combination (caffeinol) was effective after either oral pretreatment or intravenous administration starting up to 2 hours after stroke onset. Ethanol alone aggravated ischemic damage, while caffeine alone was without effect. Daily caffeinol for 2 weeks before ischemia eliminated the neuroprotection seen with acute treatment (tolerance). The purpose of our present study was to further characterize the properties of caffeinol as a possible treatment for ischemic stroke.Methods-The transient CCA/MCA occlusion model was used in all experiments. Five sets of experiments were conducted (1) to test the effectiveness of various doses of ethanol (0.2 to 0.65 g/kg) and caffeine (3 to 10 mg/kg) in the caffeinol mixture; (2) to test whether the neuroprotective dose of caffeinol can improve behavioral dysfunction; (3) to test whether chronic ethanol or caffeine before ischemia will affect efficacy of caffeinol treatment; (4) to test whether the protective effect of caffeinol can be improved by pairing it with 35degreesC hypothermia; and (5) to test whether caffeinol affects frequency of hemorrhage after administration of recombinant tissue plasminogen activator (rtPA) in ischemic animals.Results-Doses as low as 0.2 g/kg of ethanol and 6 mg/kg of caffeine in the caffeinol were effective in reducing cortical infarct volume and behavioral dysfunction after transient CCA/MCA occlusion. Daily exposure to ethanol but not caffeine before CCA/MCA occlusion eliminated the therapeutic efficacy of acute caffeinol treatment, similar to the tolerance observed after chronic exposure to caffeinol. The therapeutic effect of caffeinol could be further improved by pairing it with mild intraischemic hypothermia, and caffeinol did not increase hemorrhagic infarction when given in combination with rtPA.Conclusions-Low doses of caffeinol, equivalent to no more than 2 to 3 cups of strong coffee and 1 cocktail, are consistently and highly neuroprotective, are well tolerated, can be added to other therapies to increase the effect of each, and do not interfere with or complicate rtPA therapy. Caffeinol is an appropriate candidate for clinical trial in stroke patients, although it may be less effective in patients with regular alcohol intake.