Progesterone improves perinatal neuromotor outcomes in a mouse model of intrauterine inflammation via immunomodulation of the placenta

Abstract

To assess the fetal neuroprotective potential of progesterone using a well-validated mouse model of lipopolysaccharide (LPS)-induced intrauterine inflammation (IUI). Embryonic day 17 pregnant mouse dams (n = 69) were randomly allocated to receive 17-hydroxyprogesterone caproate (17-OHPC), micronized progesterone (MP), or vehicle 1 hour prior to intrauterine injection of phosphate-buffered saline (PBS) or LPS. After 6 hours, mice were killed for the collection of placentas and fetal brains, or pregnancy continued for the evaluation of preterm birth (PTB) and offspring neuromotor function. Placentas and fetal brains were analyzed by mini-mRNA array for 96 immune markers with individual confirmatory qPCR. Progesterone pre-treatment before LPS-induced IUI improved neuromotor tests in offspring at PND5 compared to no pre-treatment (P < .05). In placentas, 17-OHPC, but not MP, significantly reduced CXCL9 (P < .05) with a trend toward a lower level of CXCL10. In fetal brains, 17-OHPC significantly reduced CXCL9 compared to no pre-treatment (P < .05) and IL-1β compared to pre-treatment with MP (P < .01). Progesterone pre-treatment prior to LPS-induced IUI improved offspring neuromotor outcomes. 17-OHPC, but not MP, resulted in greater immunomodulation of T cell-mediated immunity in placenta and fetal brain, suggesting a possible mechanism for the observed neuroprotective effects.

Keywords: 17-hydroxyprogesterone caproate; fetal neuroprotection; intrauterine inflammation; preterm birth; progesterone.