Adenosine has been found to act as a neuroprotective agent during ischemic brain damage. The diverse actions of adenosine are mediated through different receptors with opposing effects on the second messenger systems. The role of the different receptors subtypes have not been settled with regard to cerebral hypoxia-ischemia (HI) in the immature rat. The effects of nonselective(theophylline). A1 (DPCPX) and A2A (SCH 58261) receptor antagonists administered before or directly after neonatal HI were studied on the extent of the brain damage evaluated 14 days after the insult. HI was induced in 7-day old rats by ligation of the left carotid artery and exposure to 7.7% oxygen. The effect of theophylline (20 mg/kg) on expression of immediate early genes was studied by in situ hybridization. Theophylline (20, 30 or 60 mg/kg) given prior to HI reduced brain damage by 48% (p<0.001). 36% (p<0.01) and 34% (p<0.05), respectively, compared to control rats. This effect was not explained by changes in temperature, cerebral blood flow, blood gas/acid base status or blood glucose during the insult, but theophylline enhanced the upregulation of c-fos and reperfusion. Posttreatment with SCH 58261 (0.2 or 2 mg/kg) reduced brain damage by 19% (p<0.05) and 14% (NS), respectively, compared to control rats which was unrelated to the core temperature. DPCPX had no effect on the development of brain injury.

In conclusion, unspecific and A2A adenosine receptor antagonists reduced brain injury in an immature model of HI.