The effects of perturbations to adenosine receptor signaling in mice and newborn rats exposed to hypoxic and ischemic conditions

Adenosine is a purine nucleoside which plays an important role in many biochemical processes. In addition, it controls many central nervous system (CNS) functions both under physiological and pathophysiological conditions. Adenosine acts through four adenosine receptors (AR), of which adenosine 1 receptors (A1R) and adenosine 2A receptors (A2AR) are of particular importance in CNS. This thesis aimed to investigate adenosine`s role in two major hypoxic conditions of early and late life of humans by changing its receptor functions using receptor antagonists. These two conditions were stroke, a problem in adults/elderly and apnea, a problem of early newborns. Four studies were conducted. In the first study, we used intracortical (IC) endothelin-1 (ET-1) injection in mice to induce a cortical stroke. Using magnetic resonance imaging (MRI), we found that stroke volume was increased in transgenic (Tg) mice with over-expression of the adenosine transport protein equilibrative nucleoside transporter 1 (ENT1). Caffeine, an AR antagonist neutralized this difference. In the second study, we used ET-1 to induce cortical stroke in mice and used the selective A1R antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). Both MRI and histopathology were used to determine stroke volume. We found a greater stroke size in Tg mice treated with the A1R antagonist. In the third and fourth studies, the effect of antenatal caffeine on ontogeny of ARs and respiratory response to intermittent hypoxia was examined. Antenatal exposure to high dose caffeine caused a significant increase in A1Rs in the striatum on postnatal 1st day (P0). Also, high dose caffeine exposure caused a significant increase in gene expression of A1R and A2ARs in the brain stem (BS). These changes disappeared by postnatal 7th day (P6). There were several detrimental effects of high dose caffeine on pregnancy outcome but prenatal exposure to high dose caffeine did not change the hypoxic respiratory response of newborn rats