Neuroprotection in the Striatum of Hypoxic-Ischemic Piglets by Simultaneous Inhibition of Dopamine D1 and Adenosine A_2A Receptors

Abstract

<b><i>Introduction:</i></b> Striatal neurons of term newborns are highly vulnerable to hypoxia-ischemia (H-I). In a piglet model of H-I, a dopamine D1 receptor antagonist and an adenosine A_2A receptor antagonist alone preferentially protect striatonigral and striatopallidal neurons, respectively. Here, we tested the hypothesis whether the combined treatment with SCH23390, a D1 receptor antagonist, and SCH58261, an A_2A receptor antagonist, is more efficacious than individual D1 and A_2A receptor antagonist treatment. <b><i>Methods:</i></b> Anesthetized newborn piglets were subjected to sham operation (<i>n</i> = 6) or 40 min of hypoxia and 7 min of airway occlusion. At 5 min of reoxygenation, piglets received the vehicle, SCH23390, SCH58261, or the combined treatment (<i>n</i> = 9 in each group). At 4 days of recovery, the number of viable neurons in the entire putamen was estimated by unbiased stereology. <b><i>Results:</i></b> Stereological results showed that sham-operated piglets had an estimated 2.9 × 10⁶ neurons in the putamen, and the number of viable neurons in hypoxic-ischemic piglets was significantly reduced by 80% to 0.6 × 10⁶/putamen. Treatment with SCH23390, SCH58261, and the combination increased the numbers of viable neurons to 1.4 × 10⁶/putamen, 1.4 × 10⁶/putamen, and 2.1 × 10⁶/putamen, respectively. Notably, the combined treatment improved neuroprotection compared to individual therapy. <b><i>Conclusion:</i></b> We conclude that simultaneous inhibition of dopamine D1 receptors and adenosine A_2A receptors saves more neurons than individual treatment in the highly vulnerable putamen of a large-animal neonatal H-I model.