Assistant Professor University of Minnesota Medical School Woodbury, Minnesota, United States
Background: Hypoxic ischemic encephalopathy (HIE) is known to occur in both preterm & full-term infants resulting in cognitive and neurodevelopmental delays. There is no diagnostic biomarker or treatment for preterm HIE. Neuropeptide Y (NPY) may be a biomarker and therapeutic target. Caffeine (C) is a non-selective adenosine receptor antagonist with anti-inflammatory properties demonstrating improved neurodevelopmental outcomes in preterm infants treated for apnea of prematurity. Both NPY and C act through g-protein coupled receptors (Rs), suggesting if NPY is elevated during preterm HIE, C may inhibit NPY Rs located throughout the brain. Limited studies exist on NPY and its role in preterm HIE, and none examine response to C. Objective: This study investigates the potential of C's effectiveness as a neuroprotective agent through NPY biomarker analysis and NPY Rs expression in preterm HIE. Design/Methods: Newborn rat litters were culled to 8 pups (4F;4M), and pups were assigned to 1 of 4 groups: sham (S) (control) + normal saline (NS), S+C, hypoxic-ischemic (HI) + NS and HI+C. On postnatal day (P)7, HI was induced by carotid ligation + 8% O2 for 90min. Shams underwent a similar surgical procedure with no ligation or hypoxia. NS or C groups were given intraperitoneal injections 20 mg/kg at 0-hr post HI followed by 10 mg/kg at 24 and 48hrs post-HI. At 72hr post-HI, rats were sacrificed and plasma, hippocampus (HPC) and hypothalamus (HYP) collected. HPC & HYP mRNA expression of NPY and its Rs (Y1, Y2, Y4, Y5) using qPCR were completed. Plasma NPY levels were measured by ELISA. One-way ANOVA with Tukey’s multiple comparison tests were performed; p< 0.05 was identified as significant. Results: HYP NPY mRNA expression was increased 1.2- fold in HI vs S groups (p=0.007) and 2-fold in HI+C males vs HI+C females (p=0.04). HYP NPY mRNA expression was increased compared to HPC NPY (p=0.002). HYP Y2 Rs increased 1.7-fold among treatment groups (p=0.04). HYP Y5 Rs increased 2.1-fold in female HI-C compared to males (p=0.03). NPY plasma levels showed a non-significant trend towards elevation in female HI compared to male at P10. Additional time points are pending.
Conclusion(s): NPY is produced by the HYP, and our study reports increased mRNA expression of NPY and its Rs after preterm HI, suggesting activation of NPY. C treatment increased NPY R mRNA expression in a sex-specific manner, suggesting NPY may play a bioactive role in preterm HI and treatment response. While plasma levels appear to have limitations, NPY may represent a tissue-specific biomarker, warranting further research.
