ABSTRACT-Adenosine, a metabolite of ATP, serves a number of important physiological roles in the body. These actions contribute to sedation, bradycardia, vasorelaxation, inhibition of lipolysis and regulation of the immune system and are mediated, in part, through activation of three distinct adenosine receptor (AR) subtypes. To date, four receptor types have been cloned: A1, A2A, A2B and A3. It is becoming increasing clear that adenosine contributes significantly to cytoprotection, a function mediated principally by the A1AR and A3AR. In this review, we survey the literature on the role of adenosine and the mechanisms underlying cytoprotection and ischemic preconditioning, a process characterized by cytoprotection derived from repeated brief ischemic challenges. An important recent observation is that the expression of several AR subtypes could be regulated by oxidative stress to provide a greater cytoprotective role. Thus, like other proteins known to be regulated during ischemia, the A1AR and A3AR can be considered as being inducible receptors.

The trisomy 16 mouse fetus is a well-studied model for Down syndrome (trisomy 21), the leading genetic cause of mental retardation in the newborn population. Human chromosome 21 and mouse chromosome 16 each carry a large cluster of genes that code for components of the interferon (IFN)-alpha/beta and IFN-gamma receptors, and Down syndrome cells display significantly increased sensitivity to IFN action. We have previously reported that in utero anti-IFN IgG treatment of mice pregnant with trisomy 16 fetuses results in a significant improvement in trisomy 16 fetus growth and morphology and that anti-IFN-gamma IgG treatment can prevent the premature death of trisomy 16 fetal mouse cortical neurons in culture. We have now used IFN receptor subunit knockout mice to produce mouse fetuses that carry three No. 16 chromosomes and one copy each of disabled IFN-gamma receptor (IFNGR) and IFN-alpha/beta receptor (IFNAR-2) component genes. We report here that this partial IFN receptor knockout trisomy (PIRKOT) mouse fetus has significantly improved growth and yields cortical neurons whose viability is the equivalent of that seen in their euploid counterparts.

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