(854) GDF-15 Exacerbates Hypoxic-Ischemic Brain Injury in Neonatal Male Mice

Introduction: Growth differentiation factor 15 (GDF-15), also known as macrophage inhibitory cytokine-1, is an immunomodulatory hormone increased after tissue injury. Whether GDF-15 is beneficial or maladaptive during stress may depend on a variety of factors including disease etiology, target organ, or patient characteristics. Moreover, the role of GDF-15 in neonatal hypoxic-ischemic encephalopathy (HIE) has not been explored. We evaluated the impact of total body GDF-15 knock-out (KO) on the extent of brain injury in male and female mice in the Rice-Vannucci (RV) model of perinatal hypoxia-ischemia (HI).

Methods: C57BL/6-Gdf15tm1(cre/ERT2)Amc/J KO mice were purchased from Jackson laboratories and bred at the University of Pittsburgh. On PND 9-11, wild-type (WT), heterozygote (Het) or KOs (n=5-6/sex/group) underwent HI via right common carotid artery ligation and 25 min of hypoxia (8% O2/92% N2)–or sham procedures. Hippocampal volume (normalized to the uninjured hippocampus) was measured at 7d post-injury. Data were analyzed by 2-way ANOVA (dichotomized by sex) and Tukey’s post-hoc test.

Results: 70 mice were analyzed. Male WT pups had increased hippocampal volume loss after HI vs. shams [median 62.53% (IQR: 17.02-100.0) vs. 4.50% (-3.54-8.95), P< 0.01]. There was no difference in male GDF-15 KO pups after HI compared to shams [31.85% (12.32-35.69) vs. -3.73% (-9.74-8.11), P=0.34]. Male Het pups had an intermediate phenotype [HI: 24.98% (18.79-59.27) vs. sham: 0.44% (-4.36-6.33), P=0.07]. There was a trend towards greater loss in WTs vs. KOs after HI (P=0.14). There was no difference in female WT volume loss after HI vs. shams [18.53% (15.06-26.00) vs. 5.47% (-2.87-9.93), P=0.29]. There was significant volume loss in female Het pups after HI vs. shams [23.07% (10.12-44.94) vs. 1.35% (-0.85-7.65), P< 0.05], but not in female KO pups vs. KO shams [32.26% (12.19-36.38) vs 2.75% (0.24-6.80), P=0.07].

Conclusions: Male GDF-15 KO pups had tissue sparing after HI compared to WTs. Future studies should investigate if downstream neuroinflammatory signaling are differentially modulated in the male vs. female brain in GDF-15 KOs, and if the neuroprotective phenotype is age-dependent.