Pre- and peristroke treatment with the adenosine kinase inhibitor, 5'-deoxyiodotubercidin, significantly reduces infarct volume after temporary occlusion of the middle cerebral artery in rats.
The adenosine kinase inhibitor, 5'-deoxyiodotubercidin (5dITU), was examined in a rat focal stoke model with temporary (105 min) middle cerebral artery occlusion (MCAO) followed by a 24 h recovery period. Inhibition of this adenosine metabolizing enzyme indirectly enhances the actions of endogenous adenosine without inducing cardiovascular side effects. Such effects could limit the potential clinical application of any approach targeting adenosine receptor activation. MCAO was accomplished with a transluminal 4-0 nylon suture inserted through the common carotid artery to block blood flow at the origin of the MCA. Treatment with 5dITU 30 min prior to and 5 h after MCAO resulted in a dose dependent (0.1-0.5 mg/kg, i.p.) reduction in infarct volume. A significant (P = 0.02) 44% reduction (control, 265 +/- 35 mm3; treated, 149 +/- 30 mm3) was observed at 0.5 mg/kg. However, at the highest dose examined (1.0 mg/kg) infarct volume was unaffected. To assess the potential for acute (i.e. post-occlusion) treatment, 5dITU was administered (0.33 mg/kg, i.v.) successively at each of 0.5, 1.75 and 3.5 h after MCAO. Post-occlusion treatment resulted in a significant (P = 0.037) 32% reduction in infarct volume (control, 314 +/- 34 mm3; treated, 212 +/- 28 mm3). At this dose there were no apparent changes in a number of physiological parameters monitored over the period of MCAO. The present study shows that intervention with an adenosine kinase inhibitor in an ischemic brain injury model is neuroprotective whether treatment is begun prior to or just after MCAO.
Miller
L P
LP
Research Department, Gensia, Inc., San Diego, CA 92121, USA. len.miller@gensia.com
Jelovich
L A
LA
Yao
L
L
DaRe
J
J
Ugarkar
B
B
Foster
A C
AC
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D002536:Cerebral Arteries; D002544:Cerebral Infarction / Q000188:drug therapy*; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D003251:Constriction, Pathologic; D008297:Male; D051381:Rats; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000627:therapeutic use
C040541:5'-deoxy-5-iodotubercidin; D000248:Adenosine Kinase; D014372:Tubercidin