Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience.
OBJECTIVE
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 degrees 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.
Aronowski
Jaroslaw
J
Stroke Program, Department of Neurology, University of Texas at Houston Medical School, Houston, 77030, USA. J.Aronowski@uth.tmc.edu
Strong
Roger
R
Shirzadi
Ali
A
Grotta
James C
JC
D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D017536:Carotid Artery, Common; D002543:Cerebral Hemorrhage / Q000139:chemically induced; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D007036:Hypothermia, Induced; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D011434:Proprioception / Q000187:drug effects; D051381:Rats; D012018:Reflex / Q000187:drug effects; D016037:Single-Blind Method; D015912:Thrombolytic Therapy / Q000009:adverse effects; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D002110:Caffeine; D000431:Ethanol; D010959:Tissue Plasminogen Activator