11 - Human Chorionic Gonadotropin Prevents Brain Injury in Neonatal Mice Subjected to Hypoxia and Systemic Inflammation

Poster Number: 11
Publication Number: 11.433

Alexander Crider, Washington University in St. Louis School of Medicine, St. Louis, MO, United States; Rafael Galindo, Washington University in St. Louis, De Peres, MO, United States; Ben D. Miller, Washington University in St. Louis, Wynnewood, PA, United States; Bhooma R. Aravamuthan, Washington University in St. Louis School of Medicine, St. Louis City, MO, United States

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of poor neurodevelopmental outcomes in newborns. Currently, therapeutic hypothermia is the only effective treatment for neonatal encephalopathy caused by HIE. However, infants with HIE suffer worse neurological outcomes in the setting of systemic inflammation (sepsis, chorioamnionitis, etc.) despite treatment with therapeutic hypothermia. Therefore, there is a need to develop novel strategies to prevent brain injury in neonatal HIE. Previous work by our lab has shown that hCG protects against brain injury in neonatal mice subjected to hypoxia and unilateral carotid ligation. Work by others has shown that hCG reduces systemic inflammation both naturally in pregnancy and when administered exogenously in animal models.

Objective: We hypothesize that exogenous hCG will reduce brain injury in a mouse model of newborn HIE potentiated by systemic inflammation.

Design/Methods: Newborn mice age postnatal day 8 were given an intraperitoneal injection of either hCG (1.5 IU/g) or saline followed 2 hours later by an intraperitoneal injection of lipopolysaccharide (LPS) (0.6 ug/g). Eighteen hours later, the left carotid artery was ligated and the mice were placed in 8% oxygen for twenty minutes. Seven days later, their brains were extracted, fixed in formaldehyde, and cut into 50 micron sections. Relative size of brain structures were measured in addition to immune staining for Iba1 and parvalbumin.

Results: Neonatal mice at postnatal day 8 who received hCG prior to being subjected to LPS, carotid ligation, and hypoxia showed significantly less brain injury than those treated with vehicle control by multiple different measures. Mice treated with hCG demonstrated significantly less cortical cystic lesions and volume loss (25.6 vs. 7.6 ± 6.9 % tissue loss; p=0.023). Treated mice also preserved parvalbumin positive neurons in both the cortex, striatum, and CA3 region of the hippocampus. Finally, hCG-treated mice had significantly less microglial activation in the hippocampus compared to vehicle-treated control as demonstrated by decreased Iba1 staining (1.4 vs 2.3 ± 0.37 fold increase in Iba1 staining over uninjured side; p=0.045).

Conclusion(s):

hCG decreases the amount of brain injury in newborn mice subjected to hypoxia-ischemia and systemic inflammation induced by LPS. hCG prevents cortical tissue loss, promotes survival of parvalbumin positive neurons, and decreases microglial activation in these mice.