Published Online
on February 27, 2003

A more recent version of this article appeared on March 1, 2003

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Submitted on October 7, 2002
Accepted on October 9, 2002

Aggravated Brain Damage After Hypoxic Ischemia in Immature Adenosine A_2A Knockout Mice

Ulrika Ådén MD, PhD^*; Linda Halldner MD; Hugo Lagercrantz MD, PhD; Ishar Dalmau MD, PhD; Catherine Ledent PhD; and Bertil B. Fredholm PhD

From the Departments of Physiology and Pharmacology (U.Å., L.H., B.B.F.) and Woman and Child Health (U.Å., H.L.), Karolinska Institutet, Stockholm, Sweden; Unit of Histology, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain (I.D.); and IRIBHN, Université libre de Bruxelles, Brussels, Belgium (C.L.).

^* To whom correspondence should be addressed. E-mail: ulrika.aden{at}fyfa.ki.se.

Background and Purpose--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 A_2A receptors (A2AR) using 7-day-old A_2A 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.

Key words: behavior • cerebral ischemia • hypoxia • newborn • mice

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