Effects of nitrobenzylthioinosine on adenosine levels and neuronal injury in rat forebrain ischemia

Nitrobenzylthioinosine (NBMPR) can potentiate the actions of adenosine through inhibition of adenosine influx mediated by the equilibrative nucleoside transporter subtype 1 (ENT1). As adenosine can decrease ischemic neuronal injury, we tested the hypothesis that peripheral administration of the pro-drug NBMPR-phosphate (NBMPR-P) can increase brain adenosine levels and reduce ischemia-induced loss of hippocampal CA1 neurons. Pre-ischemic, but not post-ischemic, peripheral administration of NBMPR-P significantly (P = 0.03) increased neuronal survival. Mechanistically, NBMPR-induced neuroprotection was associated with significant (P = 0.03) increases in adenosine levels relative to saline-treated controls. Hypothermia was tested for but did not account for the beneficial effects of NBMPR. Together, these data suggest that selective inhibition of ENT1 adenosine transporters can increase post-ischemic levels of adenosine and reduce ischemic neuronal death.