Adenosine kinase inhibition protects brain against transient focal ischemia in rats.
Endogenous adenosine released locally during cerebral ischemia is neuroprotective, and agents which decrease adenosine inactivation may potentiate its protective effects. The effects of 5'-deoxy-5-iodotubercidin (5'd-5IT), an inhibitor of the adenosine-catabolizing enzyme, adenosine kinase, were studied in male Wistar rats subjected to 2 h of transient middle cerebral artery occlusion. 5'd-5IT or the vehicle (10% DMSO in saline) was administered i.p. 30 min before, and 2 h and 6 h after the induction of middle cerebral artery occlusion. The infarct volume was determine using 2,3,5-triphenyltetrazolium chloride staining 48 h after middle cerebral artery occlusion. The infarct volume was significantly reduced in rats treated with 1.85 mg/kg x 3 (57% reduction, P < 0.001) or 1.0 mg/kg x 3 (34% reduction, P < 0.05), but not 0.3 mg/kg x 3 5'd-5IT compared to vehicle-treated rats. The reduction of infarct volume was accompanied by a significant improvement in behavioral measures of neurological deficit. These data further support a role of adenosine in neuroprotection and suggest that adenosine kinase inhibition may be a useful approach to the treatment of focal cerebral ischemia.
Jiang
N
N
Henry Ford Health Science Center, Department of Neurology, Detroit, MI 48202, USA.
Kowaluk
E A
EA
Lee
C H
CH
Mazdiyasni
H
H
Chopp
M
M
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000627:therapeutic use
C040541:5'-deoxy-5-iodotubercidin; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D000248:Adenosine Kinase; D014372:Tubercidin