Neuroprotection in the Striatum of Hypoxic-Ischemic Piglets by Simultaneous Inhibition of Dopamine D1 and Adenosine A2A Receptors.

INTRODUCTION

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 A2A 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 A2A receptor antagonist, is more efficacious than individual D1 and A2A receptor antagonist treatment.

METHODS

Anesthetized newborn piglets were subjected to sham operation (n = 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 (n = 9 in each group). At 4 days of recovery, the number of viable neurons in the entire putamen was estimated by unbiased stereology.

RESULTS

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.

CONCLUSION

We conclude that simultaneous inhibition of dopamine D1 receptors and adenosine A2A receptors saves more neurons than individual treatment in the highly vulnerable putamen of a large-animal neonatal H-I model.