Activation of adenosine A3 receptors reduces ischemic brain injury in rodents.
Adenosine A3 receptor (A3R) agonists have been shown to reduce cardiac and lung injury, but the protective roles of A3R agonists in the CNS are not well characterized. The protective effect of selective A3R agonist chloro-N(6)-(3-iodo-benzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) was first examined in primary cortical cultures. In cortical culture, Cl-IB-MECA pretreatment antagonized the hypoxia-mediated decrease in cell viability. In vivo, Cl-IB-MECA or vehicle was given intracerebroventricularly or intravenously to anesthetized rats. Animals were subjected to focal cerebral ischemia induced by transient middle cerebral artery (MCA) ligation. Intracerebroventricular or repeated intravenous administration (i.e., at 165 min and 15 min before MCA ligation) of Cl-IB-MECA did not alter blood pressure during ischemia but increased locomotor activity and decreased cerebral infarction 2 days after. In these animals, Cl-IB-MECA also reduced the density of TUNEL labeling in the lesioned cortex. The possibility of endogeneous neuroprotection was further examined in A3R knockout mice. After MCA ligation, an increase in cerebral infarction was found in the A3R knockouts compared with the A3R wild-type controls, suggesting that A3Rs are tonically activated during ischemia. Additionally, intracerebroventricular pretreatment with Cl-IB-MECA decreased the size of infarction in the wild-type controls, but not in the A3R knockout animals, suggesting that Cl-IB-MECA-induced protection was mediated through the A3 receptors. Collectively, these data suggest that Cl-IB-MECA reduced cerebral infarction through the activation of A3Rs and suppression of apoptosis.
Chen
Guann-Juh
GJ
National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA.
Harvey
Brandon K
BK
Shen
Hui
H
Chou
Jenny
J
Victor
Adrienne
A
Wang
Yun
Y
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D001794:Blood Pressure / Q000187:drug effects; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D043684:Receptor, Adenosine A3 / Q000378:metabolism* / Q000502:physiology; D013778:Tetrazolium Salts
D043684:Receptor, Adenosine A3; D013778:Tetrazolium Salts; C046756:5'-N-methylcarboxamideadenosine; C009591:triphenyltetrazolium; D000241:Adenosine