Ethanol Plus Caffeine (Caffeinol) for Treatment of Ischemic Stroke

Abstract

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 35°C 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.

Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia

“…This has sometimes been referred to as the "cocktail" approach [1,39]. With the use of multiple neuroprotective therapies, each agent could be given either simultaneously or in rapid succession, allowing each agent to work on a different ischemic injury mechanism [2,3,5,7,8,17,26,29,32]. Therefore we suggest that a "combotemporal stroke therapy", such as the combined use of a neuroprotective or anti-inflammatory agent and an excitatory amino acid antagonist simultaneously or in sequence, may provide greater neuroprotection than either agent alone.…”

Clinical trials for cytoprotection in stroke

“…TPA with caffeinol imparts no increased risk of intracranial hemorrhage in vivo, and no reduction of TPA fibrinolytic activity in vitro. 213 The protective effect of caffeinol has recently been confirmed in the suture model of transient MCA occlusion, with the predominant effect on cortical salvage. The protective mechanism is likely due to the synergistic effect of caffeine and ethanol on the excitatory/inhibitory balance between neurotransmitter systems.…”

“…213 In this model, hypothermia was started 60 min after the onset of ischemia and continued for 240 min. A pilot study designed to establish the feasibility and safety of administering both caffeinol and mild systemic hypothermia in acute ischemic stroke patients treated with i.v.…”

Experimental neuroprotection in ischemic stroke: a concise review

“…Aronowski et al, 3 utilizing a rat model of common carotid artery/left MCA infarct, treated different cohorts with combinations of ethanol, caffeine, and hypothermia. They concluded that low doses of caffeine, equivalent to 2-3 cups of coffee, and low doses of ethanol, equivalent to 1 cocktail, are highly neuroprotective and can reduce cortical infarct volumes and behavioral dysfunction after transient occlusion.…”