title: Caffeinol at the receptor level: anti-ischemic effect of N-methyl-D-aspartate receptor blockade is potentiated by caffeine.
abstract: OBJECTIVE
  Although caffeinol (a combination of a low dose of caffeine and ethanol) was shown to robustly reduce stroke damage in experimental models and is now in clinical evaluation for treatment of ischemic stroke, little is known about the potential mechanism of its action.
  
  
  METHODS
  We used an in vivo excitotoxicity model based on intracortical infusion of N-methyl-D-aspartate (NMDA) and a model of reversible focal ischemia to demonstrate NMDA receptor inhibition as a potential mechanism of caffeinol anti-ischemic activity.
  
  
  RESULTS
  Caffeinol reduced the size of excitotoxic lesion, and substitution of ethanol in caffeinol with the NMDA antagonists CNS-1102 and MK-801 but not with MgSO(4) produced treatment with strong synergistic effect that was at least as robust in reducing ischemic damage as caffeinol. This NMDA receptor antagonist and caffeine combination demonstrated a long window of opportunity, activity in spontaneously hypertensive rats, and, unlike caffeinol, was fully effective in animals chronically pretreated with ethanol.
  
  
  CONCLUSIONS
  Our study suggests that antiexcitotoxic properties may underlie some of the anti-ischemic effect of caffeinol. This study provides strong evidence that the anti-ischemic effect of NMDA receptor blockers in general can be dramatically augmented by caffeine, thus opening a possibility for new use of NMDA-based pharmacology in the treatment of stroke.
authors.affiliation: Stroke Program, Department of Neurology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Xiurong
authors.initials: X
authors.lastname: Zhao
authors.forename: Roger
authors.initials: R
authors.lastname: Strong
authors.forename: Paisith
authors.initials: P
authors.lastname: Piriyawat
authors.forename: Robert
authors.initials: R
authors.lastname: Palusinski
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Aronowski
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology* / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010726:Phosphodiesterase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C503306:caffeinol; D002110:Caffeine; D000431:Ethanol; C079779:aptiganel; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate