Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice.
OBJECTIVE
Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant. Adenosine is believed to protect against HI brain damage. However, the roles of the different adenosine receptors are unclear, particularly in young animals. We examined the role of adenosine A2A receptors (A2AR) using 7-day-old A2A knockout (A2AR(-/-)) mice in a model of HI.


METHODS
HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30 minutes after occlusion of the left common carotid artery. The resulting unilateral focal lesion was evaluated with the use of histopathological scoring and measurements of residual brain areas at 5 days, 3 weeks, and 3 months after HI. Behavioral evaluation of brain injury by locomotor activity, rotarod, and beam-walking test was made 3 weeks and 3 months after HI. Cortical cerebral blood flow, assessed by laser-Doppler flowmetry, and rectal temperature were measured during HI.


RESULTS
Reduction in cortical cerebral blood flow during HI and rectal temperature did not differ between wild-type (A2AR(+/+)) and knockout mice. In the A2AR(-/-) animals, brain injury was aggravated compared with wild-type mice. The A2AR(-/-) mice subjected to HI displayed increased forward locomotion and impaired rotarod performance in adulthood compared with A2AR(+/+) mice subjected to HI, whereas beam-walking performance was similarly defective in both groups.


CONCLUSIONS
These results suggest that, in contrast to the situation in adult animals, A2AR play an important protective role in neonatal HI brain injury.
Adén
Ulrika
U
Department of Physiology and Pharmacology, Karolinska Institutet, S-171 76 Stockholm, Sweden. ulrika.aden@fyfa.ki.se
Halldner
Linda
L
Lagercrantz
Hugo
H
Dalmau
Ishar
I
Ledent
Catherine
C
Fredholm
Bertil B
BB
D000818:Animals; D000831:Animals, Newborn; D001273:Atmosphere Exposure Chambers; D001522:Behavior, Animal; D001783:Blood Flow Velocity; D001831:Body Temperature; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology*; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D018450:Disease Progression; D002534:Hypoxia, Brain / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000172:deficiency* / Q000235:genetics; D015996:Survival Rate
D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1